KR101384927B1 - Novel dihydropseudoerythromycin derivatives - Google Patents

Abstract

A compound represented by the formula [I] wherein each symbol is as defined in the specification or a pharmacologically acceptable salt thereof, and a pharmaceutical composition containing the compound as an active ingredient.

Description

New Dehydroshudoerythromycin Derivatives {NOVEL DIHYDROPSEUDOERYTHROMYCIN DERIVATIVES}

The present invention relates to novel dihydroshudoerythromycin derivatives. In particular, the present invention relates to novel dihydroshudoerythromycin derivatives which are excellent in anti-inflammatory action and stable.

Erythromycin (14-membered ring macrolide) is difficult to use as an anti-inflammatory because it simultaneously acts as an anti-inflammatory and antibacterial action. To solve this problem, Pseudoerythromycin derivatives which are anti-inflammatory but not antibacterial (12-membered rings, EM700 series of Kitasato Research Institute, International Publication No. WO2002 / 14338 and No. WO2004 / 39823) have been reported. Representative compound is EM703 represented by the following formula.

Since the pseudoerythromycin derivatives mentioned above are partially decomposed by acid and relatively unstable, there is a problem that the pharmacological action may not be sufficiently exerted upon oral administration.

The dihydro form obtained by reduction to solve the above problem is stable to acid and shows good pharmacological action upon oral administration. Faghih R, Nellans HN, Lartey PA, Petersen A, Marsh K, Bennani YL, Plattner JJ. Preparation of 9-deoxo-4 "-deoxy-6,9-epoxyerythromycin lactams“ motilactides ”: potent and orally active prokinetic agents.Bioorg Med Chem Lett. 1998, 8 (7): 805-10 contains a dehydroshudoerythromycin derivative. Although all of them are cladinoses (sugars in 3-position) in the form of 4 "-dehydroxy. Although the literature describes that dihydroshudoerythromycin derivatives exhibit weak gastrointestinal motility-promoting activity, no anti-inflammatory action is described.

DISCLOSURE OF INVENTION

The present invention aims to develop a compound which avoids the antibacterial action of erythromycin and has only anti-inflammatory action, in particular, a stable pseudoerythromycin derivative.

The present inventors carried out an intensive study to solve the above problem by avoiding the antimicrobial action using a 12-membered ring and further reducing the compound to produce a dihydro form, to succeed in improving the stability to the acid, the present invention Came to complete. Accordingly, the present invention provides the following.

[1] a compound represented by the following formula [I], or a pharmacologically acceptable salt thereof:

{Wherein Me is a methyl group,

R ₁ and R ₂ are the same or different and each is a hydrogen atom, an alkyl group, an acyl group, a sulfonyl group, a substituted or unsubstituted aryl-substituted alkyl group, an aryl-substituted alkyloxycarbonyl group, an alkenyl group or an alkynyl group, or R ₁ and R the _two are combined, adjacent to form a substituted or unsubstituted alicyclic heterocyclic group together with the nitrogen atom,

R ₃ is a hydrogen atom, a substituted or unsubstituted acyl group or an aryl-substituted alkyloxycarbonyl group, A is a hydrogen atom, B is a hydroxyl group or a group represented by the following formula [II]

(Wherein Me is a methyl group and R ₄ is a hydrogen atom or an acyl group), or A and B in combination represent = O,

R is a group represented by the following general formula [III]

(Wherein Me is a methyl group, R ₅ and R ₆ are the same or different and each represents a hydrogen atom or an acyl group, or R ₅ and R ₆ in combination represent a carbonyl group or a substituted or unsubstituted alkylene group), Or a substituent represented by [IV]

(Wherein Me is a methyl group, D is O or N-OH, or D is a hydrogen atom and a hydroxyl group (-H, -OH)), or a substituent represented by the following formula [V]:

(Wherein Me is a methyl group)}.

[2] The compound of [1], or a pharmacologically acceptable salt thereof, wherein R is a group represented by the following formula [III]:

(Wherein Me is a methyl group, R ₅ and R ₆ are the same or different and each represents a hydrogen atom or an acyl group, or R ₅ and R ₆ in combination represent a carbonyl group or a substituted or unsubstituted alkylene group).

[3] The compound of [1] or [2], or a pharmacologically acceptable salt thereof, wherein A and B in combination represent = O.

[4] The compound of [1] or [2], or a pharmacologically acceptable salt thereof, wherein A is a hydrogen atom and B is a hydroxyl group.

[5] The compound of [1] or [2], or a pharmacologically acceptable salt thereof, wherein A is a hydrogen atom and B is a group represented by the following formula [II]:

(Wherein Me is a methyl group and R ₄ is a hydrogen atom or an acyl group).

[6] The compound of [5], or a pharmacologically acceptable salt thereof, wherein R ₄ is a hydrogen atom.

[7] R ₁ and R ₂ are the same or different and each is a hydrogen atom, an alkyl group, a substituted or unsubstituted benzyl group or a benzyloxycarbonyl group, or R ₁ and R ₂ are combined and substituted or unsubstituted with an adjacent nitrogen atom. The compound of any one of the above [1] to [6], or a pharmacologically acceptable salt thereof, for forming an alicyclic heterocyclic group.

[8] The compound of [7], or a pharmacologically acceptable salt thereof, wherein R ₁ and R ₂ are the same or different and each is a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms, or a halogen-substituted benzyl group.

[9] The substituted or unsubstituted alicyclic heterocyclic group formed by combining R ₁ and R ₂ with an adjacent nitrogen atom is a substituted or unsubstituted morpholine ring, piperidine ring, piperazine ring or pyrrolidine ring. The compound of [7], or a pharmacologically acceptable salt thereof.

[10] The compound of any one of the above [1] to [9], or a pharmacologically acceptable salt thereof, wherein R ₃ is a hydrogen atom, an acetyl group, a substituted or unsubstituted benzoyl group, or a benzyloxycarbonyl group.

[11] The compound of the above [10], or a pharmacologically acceptable salt thereof, wherein R ₃ is a hydrogen atom, a substituted or unsubstituted acetyl group, or a benzoyl group.

[12] the following compound, or a pharmacologically acceptable salt thereof:

(1) 9-dihydro-pseudoerythromycin A 6,9-epoxide

(2) de (3'-N-methyl) -9-dihydro- pseudoerythromycin A 6,9-epoxide

(3) de (3'-N-methyl) -3'-N-benzyl-9-dihydro- pseudoerythromycin A 6,9-epoxide

(4) bis-de (3'-N-methyl) -9-dihydro- pseudoerythromycin A 6,9-epoxide

(5) Bis-de (3'-N-methyl) -bis- (3'-N-benzyl) -9-dihydro- pseudoerythromycin A 6,9-epoxide

(6) de (3'-N-methyl) -3'-N- (p-chlorobenzyl) -9-dihydro- pseudoerythromycin A 6,9-epoxide

(7) de [12- (1-hydroxypropyl)]-9-dihydro-12-oxo- pseudoerythromycin A 6,9-epoxide

(8) de [12- (1-hydroxypropyl)]-9-dihydro-12-hydroxyoxime- pseudoerythromycin A 6,9-epoxide

(9) de [12- (1-hydroxypropyl)]-9-dihydro- pseudoerythromycin A 6,9-epoxide

(10) 12,13-epoxy-9-dihydro-pseudoerythromycin A 6,9-epoxide

(11) de (3-O-cladinosyl) -9-dihydro- pseudoerythromycin A 6,9-epoxide

(12) 4 ", 13-O-diacetyl-9-dihydro- pseudoerythromycin A 6,9-epoxide

(13) 2'-0-acetyl-9-dihydro-pseudoerythromycin A 6,9-epoxide

(14) de (3'-dimethylamino) -3'-morpholino-9-dihydro-pseudoerythromycin A 6,9-epoxide

(15) 2'-O-acetyl-de (3-O-cladinosyl) -9-dihydro-3-keto- pseudoerythromycin A 6,9-epoxide 12,13-carbonate

(16) de (3-O-cladinosyl) -9-dihydro-3-keto- pseudoerythromycin A 6,9-epoxide 12,13-carbonate

(17) de (3'-N-methyl) -3'-N- (p-chlorobenzyl) -de (3-O-cladinosyl) -9-dihydro-pseudoerythromycin A 6,9-epoxy De

(18) 2'-O-acetyl-de (3-O-cladinosyl) -9-dihydro-3-keto-de (3'-dimethylamino) -3'-morpholino- pseudoerythromycin A 6,9-epoxide 12,13-carbonate

(19) de (3-O-cladinosyl) -9-dihydro-3-keto-de (3'-dimethylamino) -3'-morpholino-pseudoerythromycin A 6,9-epoxide 12 , 13-carbonate

(20) de (3'-N-methyl) -2'-O-3'-N-bis (benzyloxycarbonyl) -de (3-O-cladinosyl) -9-dihydro- pseudoerythromycin A 6,9-epoxide 12,13-carbonate

(21) de (3'-N-methyl) -3'-N- (p-chlorobenzyl) -de (3-O-cladinosyl) -9-dihydro-3-keto- pseudoerythromycin A 6 , 9-epoxide 12,13-carbonate

(22) de (3-O-cladinosyl) -9-dihydro-de (3'-dimethylamino) -3'-morpholino- pseudoerythromycin A 6,9-epoxide 12,13-carr Bonate

(23) de (3'-N-methyl) -3'-N- (p-chlorobenzyl) -de (3-O-cladinosyl) -9-dihydro-3-keto- pseudoerythromycin A 6 , 9-epoxide 12,13-isopropylidene acetal or

(24) de (3'-N-methyl) -3'-N- (p-chlorobenzyl) -de (3-O-cladinosyl) -9-dihydro-3-keto- pseudoerythromycin A 6 , 9-epoxide.

[13] the following compound, or pharmacologically acceptable salt thereof:

(1) de (3'-N-methyl) -3'-N- (p-chlorobenzyl) -9-dihydro- pseudoerythromycin A 6,9-epoxide

(2) de (3'-dimethylamino) -3'-morpholino-9-dihydro- pseudoerythromycin A 6,9-epoxide or

(3) de (3'-N-methyl) -3'-N- (p-chlorobenzyl) -de (3-O-cladinosyl) -9-dihydro-3-keto- pseudoerythromycin A 6 , 9-epoxide 12,13-carbonate.

[14] A pharmaceutical composition comprising the compound of any one of [1] to [13] or a pharmacologically acceptable salt thereof as an active ingredient.

[15] The pharmaceutical composition of [14], which is used for preventing or treating an inflammatory disease.

[16] The pharmaceutical composition of [15], wherein the inflammatory disease is inflammatory bowel disease.

[17] A method for preventing or treating an inflammatory disease, comprising administering to a patient in need thereof an effective amount of the compound of any one of the above [1] to [13] or a pharmacologically acceptable salt thereof.

[18] The method of [17], wherein the inflammatory disease is inflammatory bowel disease.

[19] Use of the compound of any one of [1] to [13] or a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical preparation for preventing or treating an inflammatory disease.

[20] The use of the above-mentioned [19], wherein the inflammatory disease is an inflammatory bowel disease.

[21] An agent for the prophylaxis or treatment of an inflammatory disease, comprising the compound of any one of the above [1] to [13] or a pharmacologically acceptable salt thereof, and the agent for the prophylaxis or treatment of an inflammatory disease Commercial package containing documentation that can be used or should be used.

DETAILED DESCRIPTION OF THE INVENTION

In the compound represented by the formula [I], the stereostructures at the 8-position and 9-position are not particularly limited. Compounds of the invention encompass all stereoisomers at the 8- and 9-positions.

In the present specification, an "alkyl group" is a straight or branched chain alkyl group having 1 to 12 carbon atoms or a cyclic alkyl group having 3 to 10 carbon atoms. Examples thereof include methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group, n-unde Real group, n-dodecyl group, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, isopentyl group, tert-pentyl group, neopentyl group, 2-pentyl group, 3-pentyl group, 2- Hexyl group, tert-octyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, 1-adamantyl group, etc., C1-C3 lower alkyl group (methyl group, ethyl group, n-propyl group) Etc.) is preferable.

In the present specification, an "acyl group" is an acyl group having a formyl group, a straight or branched chain alkyl group having 1 to 12 carbon atoms, or a cyclic alkyl group having 3 to 10 carbon atoms, a straight or branched chain alkenyl group having 2 to 12 carbon atoms, or 3 to carbon atoms. It is an acyl group which has a 10 cyclic alkenyl group, or the acyl group which has a C6-C14 aryl group. As used herein, an aryl group is a monocyclic-tricyclic aromatic hydrocarbon group having 6 to 14 carbon atoms. Examples thereof include phenyl group, biphenyl group, naphthyl group, anthryl group, phenanthryl group and the like. Examples of the acyl group are formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, acryloyl, methacryloyl, crotonoyl and iso It is a crotonoyl group, a benzoyl group, a naphthoyl group, etc., and an acetyl group and a benzoyl group are preferable.

As used herein, "substituted or unsubstituted acyl group" means an unsubstituted acyl group (as defined above) or a substituted acyl group. Examples of the substituent include a halogen (iodine, bromine, chlorine, fluorine), an alkyl group (as defined above), an alkoxy group, a hydroxyl group, a halogen-substituted alkyl group, a halogen-substituted alkoxy group, and the like, with halogen being preferred. As used herein, an alkoxy group is an alkoxy group having a straight or branched chain alkyl group having 1 to 12 carbon atoms or a cyclic alkyl group having 3 to 10 carbon atoms. Examples thereof include methoxy group, ethoxy group, propoxy group, 1-methylethoxy group, butoxy group, 2-methylpropoxy group, 1,1-dimethylethoxy group, pentoxy group, 3-methylbutoxy group, hexoxy , 4-methylpentoxy group, cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group and the like. Halogen-substituted alkyl groups and halogen-substituted alkoxy groups are alkyl groups (same as defined above) and alkoxy (same as defined above), each substituted with one or a plurality of halogens (as defined above).

As used herein, "substituted or unsubstituted aryl-substituted alkyl group" means an unsubstituted aryl-substituted alkyl group or a substituted aryl-substituted alkyl group. An "aryl-substituted alkyl group" is an alkyl group (same as defined above) substituted with an aryl group (as defined above), for example, a phenylmethyl group (benzyl group), diphenylmethyl group, triphenylmethyl group (trityl group), phenylethyl group (Phenethyl group), 3-phenylpropyl group, 2-phenylpropyl group, 4-phenylbutyl group, biphenylmethyl group, naphthylmethyl group and the like, with a benzyl group being preferred. Examples of the substituent of the aryl-substituted alkyl group include alkoxy group (same as defined above), halogen (same as defined above), alkyl group (same as defined above), hydroxyl group, halogen-substituted alkyl group (same as defined above), halogen-substituted An alkoxy group (the same as defined above) and the like, and halogen is preferred.

Unless otherwise specified, the positions and numbers of such substituents are arbitrary and not particularly limited. When substituted with two or more substituents, the substituents may be the same or different.

As used herein, “aryl-substituted alkyloxycarbonyl group” means an alkyloxycarbonyl group having a straight or branched chain alkyl group having 1 to 12 carbon atoms or a cyclic alkyl group having 3 to 10 carbon atoms, substituted with an aryl group (as defined above). do. Examples thereof include benzyloxycarbonyl group, trityloxycarbonyl group, diphenylmethyloxycarbonyl group, phenethyloxycarbonyl group and the like, and benzyloxycarbonyl group is preferable.

As used herein, "alkenyl group" means a straight or branched chain alkenyl group having 2 to 12 carbon atoms, or a cyclic alkenyl group having 3 to 10 carbon atoms and one unsaturated bond (double bond). Examples thereof include allyl group, propenyl group, butenyl group, cyclohexenyl group and the like. Allyl groups are preferred.

As used herein, "alkynyl group" means a straight or branched chain alkynyl group having 2 to 12 carbon atoms, or a cyclic alkynyl group having 3 to 10 carbon atoms and one unsaturated bond (triple bond). Examples thereof include propargyl group and 1-pentynyl group.

As used herein, "substituted or unsubstituted alicyclic heterocyclic group" means an unsubstituted alicyclic heterocyclic group or a substituted alicyclic heterocyclic group. An "alicyclic heterocycle" is a monocyclic ring with no maximum conjugated double bonds formed by carbon bonding to one or more heteroatoms such as oxygen atoms, nitrogen atoms, sulfur atoms and the like. Specific examples thereof include a pyrroline ring, a pyrrolidine ring, an imidazoline ring, an imidazolidine ring, a pyrazoline ring, a pyrazolidine ring, a piperidine ring, a piperazine ring, a morpholine ring and the like. A morpholine ring, a piperidine ring, a piperazine ring and a pyrrolidine ring are preferable, and a morpholine ring and a piperazine ring are particularly preferable. Examples of the substituent of the alicyclic heterocyclic group include an alkyl group (same as defined above), an aryl group (same as defined above), a carbonyl group (eg, the aryl-substituted alkyloxycarbonyl group) and the like.

R ₁ and R ₂ are preferably the same or different and each is a hydrogen atom, an alkyl group, a substituted or unsubstituted benzyl or benzyloxycarbonyl group, or a substitution in which R ₁ and R ₂ combine to form with an adjacent nitrogen atom or Unsubstituted alicyclic heterocyclic group. More preferably, R ₁ and R ₂ are the same or different and each is a hydrogen atom, a lower alkyl group of 1 to 3 carbon atoms or a halogen-substituted benzyl group, or R ₁ and R ₂ combine to form with adjacent nitrogen atoms Substituted or unsubstituted morpholine ring, piperidine ring, piperazine ring or pyrrolidine ring (preferably morpholine ring or piperazine ring). Examples of the substituent of the alicyclic heterocyclic group include an alkyl group (same as defined above), an aryl group (same as defined above), a carbonyl group (same as defined above), and the like. An aryl-substituted alkyloxycarbonyl group is preferable and a benzyloxycarbonyl group is more preferable.

R ₃ is preferably a hydrogen atom, an acetyl group, a substituted or unsubstituted benzoyl group, or a benzyloxycarbonyl group, and more preferably a hydrogen atom or an acetyl group.

A is a hydrogen atom, B is a hydroxyl group or a group represented by the following formula [II]

(Wherein Me is a methyl group and R ₄ is a hydrogen atom or an acyl group), or preferably A and B combine to represent = O. R ₄ is particularly preferably a hydrogen atom.

R is preferably a group represented by the following general formula [III]:

(Wherein Me is a methyl group, R ₅ and R ₆ are the same or different and each represents a hydrogen atom or an acyl group, or R ₅ and R ₆ in combination represent a carbonyl group or a substituted or unsubstituted alkylene group).

Specific examples of preferred compounds of the present invention are shown in the table below; However, the compound of the present invention is not limited thereto. In the present specification, each symbol is defined as follows.

Me: methyl group, Et: ethyl group, iPr: isopropyl group, nHex: n-hexyl group, Ac: acetyl group, Bzl: benzyl group, pCl-Bzl: benzyl group substituted with chloro group in para-position, pBr-Bzl: Benzyl group substituted with bromo group in para-position, pF-Bzl: benzyl group substituted with fluoro group in para-position, pI-Bzl: benzyl group substituted with iodine group in para-position, oCl-Bzl: ortho-position Benzyl group substituted with chloro group, mCl-Bzl: benzyl group substituted with chloro group in meta-position, pCF ₃ -Bzl: benzyl group substituted with trifluoromethyl group in para-position, pOMe-Bzl: in para-position Benzyl group substituted with methoxy group, Cbz: benzyloxycarbonyl group, pBr-Bz: benzoyl group substituted with bromo group in para-position, pMe-Bzl: benzyl group substituted with methyl group in para-position.

Table 1

Table 2

Table 3

Table 4

Table 5

Particularly preferred compounds are (1) 9-dihydro- pseudoerythromycin A 6,9-epoxide, (2) de (3'-N-methyl) -9-dihydro- pseudoerythromycin A 6,9-epoxy De, (3) de (3'-N-methyl) -3'-N-benzyl-9-dihydro- pseudoerythromycin A 6,9-epoxide, (4) bis-de (3'-N- Methyl) -9-dihydro- pseudoerythromycin A 6,9-epoxide, (5) bis-de (3'-N-methyl) -bis- (3'-N-benzyl) -9-dihydro- Pseudoerythromycin A 6,9-epoxide, (6) de (3'-N-methyl) -3'-N- (p-chlorobenzyl) -9-dihydro- pseudoerythromycin A 6,9-epoxy De, (7) de [12- (1-hydroxypropyl)]-9-dihydro-12-oxo- pseudoerythromycin A 6,9-epoxide, (8) de [12- (1-hydroxy) Propyl)]-9-dihydro-12-hydroxyoxime- pseudoerythromycin A 6,9-epoxide, (9) de [12- (1-hydroxypropyl)]-9-dihydro- pseudoerythromycin A 6,9-epoxide, (10) 12,13-epoxy-9-dihydro-pseudoerythromycin A 6,9-e Foxid (11) de (3-O-cladinosyl) -9-dihydro- pseudoerythromycin A 6,9-epoxide, (12) 4 ", 13-O-diacetyl-9-dihydro- Pseudoerythromycin A 6,9-epoxide, (13) 2'-0-acetyl-9-dihydro-pseudoerythromycin A 6,9 epoxide, (14) de (3'-dimethylamino) -3 ' -Morpholino-9-dihydro- pseudoerythromycin A 6,9-epoxide, (15) 2'-O-acetyl-de (3-O-cladinosyl) -9-dihydro-3-keto Pseudoerythromycin A 6,9-epoxide 12,13-carbonate, (16) de (3-O-cladinosyl) -9-dihydro-3-keto- pseudoerythromycin A 6,9- Epoxide 12,13-carbonate, (17) de (3'-N-methyl) -3'-N- (p-chlorobenzyl) -de (3-O-cladinosyl) -9-dihydro Pseudoerythromycin A 6,9-epoxide, (18) 2'-O-acetyl-de (3-O-cladinosyl) -9-dihydro-3-keto-de (3'-dimethylamino) -3'-morpholino- pseudoerythromycin A 6,9-epoxide 12,13-carbonate, (19) de (3-O-cla Dinosyl) -9-dihydro-3-keto-de (3'-dimethylamino) -3'-morpholino- pseudoerythromycin A 6,9-epoxide 12,13-carbonate, (20) De (3'-N-methyl) -2'-O-3'-N-bis (benzyloxycarbonyl) -de (3-O-cladinosyl) -9-dihydro- pseudoerythromycin A 6, 9-epoxide 12,13-carbonate, (21) de (3'-N-methyl) -3'-N- (p-chlorobenzyl) -de (3-O-cladinosyl) -9- Dihydro-3-keto- pseudoerythromycin A 6,9-epoxide 12,13-carbonate, (22) de (3-O-cladinosyl) -9-dihydro-de (3'-dimethyl Amino) -3'-morpholino- pseudoerythromycin A 6,9-epoxide 12,13-carbonate, (23) de (3'-N-methyl) -3'-N- (p-chloro Benzyl) -de (3-O-cladinosyl) -9-dihydro-3-keto- pseudoerythromycin A 6,9-epoxide 12,13-isopropylidene acetal, and (24) de (3 ' -N-methyl) -3'-N- (p-chlorobenzyl) -de (3-O-cladinosyl) -9-dihydro-3-keto- pseudoerythromycin A 6,9-epoxide.

More preferred compounds are de (3'-N-methyl) -3'-N- (p-chlorobenzyl) -9-dihydro- pseudoerythromycin A 6,9-epoxide, de (3'-dimethylamino) -3'-morpholino-9-dihydro-pseudoerythromycin A 6,9-epoxide, and de (3'-N-methyl) -3'-N- (p-chlorobenzyl) -de (3 -O-Cladinosyl) -9-dihydro-3-keto- pseudoerythromycin A 6,9-epoxide 12,13-carbonate.

The manufacturing method of the compound of this invention is not specifically limited, For example, it can be manufactured according to the following method. In addition, the examples herein describe in more detail the preparation of preferred compounds of the invention. Those skilled in the art can make any compound of the present invention by modifying or changing starting materials, reaction conditions, reaction reagents, etc., as appropriate, with reference to the following general description and the detailed description of the examples.

For example, among the compounds represented by the formula [I], a compound in which A is a hydrogen atom and B is a group represented by the formula [II] can be prepared according to the method shown in the following scheme.

Ie reference (a) IOKibwage, R.Busson, G. Janssen, J. Hoogmartens, H. Vanderhaeghe, Translactonization of Erythromycins, J. Org. Chem., 52, 990-996, 1987, (b) HAKirst , According to JAWind, JW Paschal, Synthesis of Ring-Constracted Derivatives of Erythromycin, J. Org. Chem. 52, 4359-4362, 1987, treating erythromycin A with glacial acetic acid to yield 8,9-anhydrous erythromycin A 6, Generate 9-hemictal (EM201). The compound is then heated to reflux in the presence of potassium carbonate in methanol to produce 8,9-anhydrous- pseudoerythromycin A 6,9-hemictal (EM701).

Next, catalytic hydrogenation is carried out using platinum oxide and difluoroacetic acid in acetic acid to synthesize 9-dihydro- pseudoerythromycin A 6,9-epoxide (EM900).

The compound is then treated with iodine and sodium acetate to produce de (3'-N-methyl) -9-dihydroshudoerythromycin A 6,9-epoxide (EM901), further with iodine and methoxide Treatment with sodium seed yields bis-de (3'-N-methyl) -9-dihydro- pseudoerythromycin A 6,9-epoxide (EM903).

With EM901 or EM903, for example, such as de (3'-N-methyl) -3'-N-benzyl-9-dihydro- pseudoerythromycin A 6,9-epoxide (EM902) Various derivatives of the compounds of the invention can be synthesized by various alkylation, acylation and the like.

On the other hand, according to the method shown, for example, in the compound represented by the above formula [I], A and B combine to represent = O, or A is a hydrogen atom and B is a hydroxyl group. can do.

Specifically, the 9-dihydroshudoerythromycin A 6,9-epoxide (EM900) was treated with benzyloxycarbonyl chloride as a starting material (3'-N-methyl) -2'-O-3 '. -N-bis (benzyloxycarbonyl) -9-dihydro- pseudoerythromycin A 6,9-epoxide (EM930) was produced and treated with hydrochloric acid in acetonitrile to give de (3'-N-methyl ) -2′-O-3′-N-bis (benzyloxycarbonyl) -de (3-O-cladinosyl) -9-dihydro- pseudoerythromycin A 6,9-epoxide (EM931) Create The EM931 was catalytically hydrogenated using a palladium hydroxide catalyst to de (3-O-cladinosyl) -de (3'-N-methyl) -9-dihydro- pseudoerythromycin A 6,9-epoxide (EM934 ) Is synthesized. EM931 was treated with triphosphene in pyridine to de (3'-N-methyl) -2'-O-3'-N-bis (benzyloxycarbonyl) -de (3-O-cladinosyl)- 9-Dihydro-Pseudoerythromycin A 6,9-epoxide 12,13-carbonate (EM936) was generated and then oxidized with Dess-Martin reagent to de (3'-N- Methyl) -2'-O-3'-N-bis (benzyloxycarbonyl) -de (3-O-cladinosyl) -9-dihydro-3-keto- pseudoerythromycin A 6,9-epoxy De 12,13-carbonate (EM937) was produced and then further catalytic hydrogenated using a palladium hydroxide catalyst to de (3-O-cladinosyl) -de (3'-N-methyl) -9- Dihydro-3-keto-pseudoerythromycin A 6,9-epoxide 12,13-carbonate (EM938) is synthesized.

Various alkylation, acylation, etc. were carried out using the EM934, EM938, and the like to form de (3'-N-methyl) -3'-N- (p-chlorobenzyl) -de (3-O-cladinosyl). Various derivatives that are compounds of the present invention, such as -9-dihydro-pseudoerythromycin A 6,9-epoxide (EM925), are synthesized.

Examples of pharmaceutically acceptable salts that may be formed by the compounds of the invention include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and the like, succinate, fumarate, acetate, methane Organic acid salts such as sulfonate, toluenesulfonate, and the like, alkali metal salts such as sodium salt, potassium salt and the like, alkaline earth metal salts such as magnesium salt and calcium salt, ammonium salts such as ammonium salt, alkyl ammonium salt and the like.

In addition, the present invention also encompasses solvates of these compounds or pharmaceutically acceptable salts thereof. Examples of the solvent include water, methanol, ethanol, isopropanol, acetone, ethyl acetate and the like.

Since the compounds of the present invention and their pharmaceutically acceptable salts exhibit excellent anti-inflammatory activity in mammals, including humans, such as cattle, horses, dogs, mice, rats, etc., they are preferably used for the prevention and treatment of inflammatory diseases. Can be. Examples of applicable diseases include, for example, inflammatory bowel disease (IBD), such as Crohn's disease, ulcerative colitis, chronic obliterative pulmonary diseases (COPD), chronic bronchitis (Chronic) bronchitis, Respiratory disease, Cystic fibrosis, Diffuse panbronchiolitis (DPB), Pneumonia, Pulmonary fibrosis, Sinusitis, Bronchiectasis ), Sinobronchial syndrome, interstitial pneumonia (Pneumonitis), Exudative otitis media, Psoriasis, Pollakiuria, Interstitial cystitis, etc. This includes.

As the active ingredient of the pharmaceutical preparation of the present invention, one or more substances selected from the above compounds and salts thereof as well as hydrates and solvates thereof may be used. The route of administration of the pharmaceutical preparation of the present invention is not particularly limited, and the preparation may be administered orally or parenterally. As a pharmaceutical formulation of the present invention, the substance may be administered directly to the patient. Preferably, however, it should be administered as a dosage form in the form of a pharmaceutical composition containing the active ingredient and pharmacological and pharmaceutically acceptable additives. Pharmacologically and pharmaceutically acceptable additives include, for example, excipients, disintegrants or disintegrants, binders, coatings, pigments, diluents, bases, solubilizers or dissolution aids, isotonic agents, pH adjusters, stabilizers, propellants, Pressure-sensitive adhesives and the like can be used. Examples of formulations suitable for oral administration include tablets, capsules, powders, granules, granules, solutions, syrups, etc. Examples of formulations suitable for parenteral administration include injections, intravenous fluids, ointments, creams, transdermal absorbents, eye drops, Ear drops, inhalants, suppositories, and the like. However, the form of the formulation is not limited thereto.

Formulations suitable for oral administration include excipients, for example, excipients such as glucose, lactose, D-mannitol, starch, crystalline cellulose and the like; Disintegrating agents or disintegrating aids such as carboxymethyl cellulose, starch, carboxymethyl cellulose calcium and the like; Binders such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, gelatin and the like; Lubricants such as magnesium stearate, talc and the like; Bases such as hydroxypropylmethylcellulose, sucrose, polyethylene glycol, gelatin, kaolin, glycerol, purified water, hard fats and the like. Formulations suitable for injectable or intravenous fluids include solubilizers or dissolution aids which may constitute aqueous injectables or injectables which dissolve in use (eg, distilled water for injection, saline, propylene glycol, etc.); Tonicity agents (eg, glucose, sodium chloride, D-mannitol, glycerol, etc.); pH adjusting agents (eg, inorganic acids, organic acids, inorganic or organic bases, etc.); And additives for formulation such as the like.

The dosage of the pharmaceutical preparation of the present invention should be varied depending on the type of disease to be applied, the purpose of prevention or treatment, the condition of the patient such as age, weight, symptoms, etc. Ingredient is about 0.05-500 mg. In general, the dosage may be administered once to several times a day, or may be administered every few days. When two or more active ingredients are included, the total amount is set within this range.

The invention is illustrated in more detail by the following starting material synthesis examples, examples, experimental examples and combination examples, which should not be construed as limiting. All publications cited throughout this invention are incorporated herein by reference in their entirety. Unless otherwise specified, reagents, devices, and materials for use in the present invention are commercially available.

Starting material Synthetic example  One

Synthesis of 8,9-Anhydrous erythromycin A 6,9-hemictal (EM201)

The glacial acetic acid solution (710.0 mL) of EMA (erythromycin A; 104.4 g, 16.90 mmol) was stirred at room temperature for 2 hours, and the aqueous solution of NaHCO ₃ was added slowly to neutralize the solution. The reaction mixture was extracted with CHCl ₃ and the organic layer was dried over Na ₂ SO ₄ . The residue was filtered and the filtrate was concentrated to yield a crude product (99.30 g). The obtained crude product was dissolved in CHCl ₃ (250 mL) and the solution was recrystallized by adding hexane (50 mL) to give EM201 (74.50 g, 71%) as a white powder.

EM201

Rf = 0.63 (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 15: 1: 0.2)

Starting material Synthetic example  2

Synthesis of 8,9-Mushudoerythromycin A 6,9-hemictal (EM701)

To a MeOH solution (150.0 mL) of EM201 (7.600 g, 10.60 mmol) was added K ₂ CO ₃ (1.400 g, 10.60 mmol) and the mixture was heated to reflux for 2 hours. After cooling to room temperature, the solvent was evaporated and the residue dissolved in aqueous NaHCO ₃ solution. The reaction mixture was extracted with CHCl ₃ and the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (9.300 g). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 10: 0.5: 0.01-10: 1: 0.05) to give EM701 of white powder (5.900 g, 78%).

EM701

Rf = 0.47 (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 15: 1: 0.2)

Example 1

Synthesis of 9-dihydro-pseudoerythromycin A 6,9-epoxide (EM900)

To acetic acid (AcOH; 7.000 mL) was added PtO ₂ (476.2 mg, 2.100 mmol) and CF ₂ HCOOH (299.0 μl, 4.750 mmol) and the mixture was stirred for 1 h at 5 atm and room temperature under H ₂ atmosphere. EM701 (1.000 g, 1.400 mmol) of AcOH solution (7.000 mL) was added and the mixture was H ₂ Stir at 5 atm and rt for 4 h under air. Then CH ₃ CO ₂ NH ₄ (7.000 g) was added, the mixture was stirred and filtered, and the filtrate was concentrated. The concentrate is extracted with CHCl ₃ and the extract is saturated NaHCO _3. Washed with aqueous solution and brine. The washed organic layer was dried over Na ₂ SO ₄ , the residue was filtered and the filtrate was concentrated to give crude product (968.4 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 50: 1: 0.02-30: 1: 0.02) to give EM900 (767.7 mg, 76%) as a white powder. It was.

EM900

Rf = 0.53 (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 15: 1: 0.2);

HR-MS m / z: 718.4767 [M + H] ⁺ , C ₃₇ H ₆₈ NO ₁₂ Calculated Value: 718.4742 [M + H]

Example  2

Synthesis of de (3'-N-methyl) -9-dihydro-pseudoerythromycin A 6,9-epoxide (EM901)

To a solution of EM900 (706.3 mg, 0.984 mmol) in methanol (MeOH) (9.840 mL) was added sodium acetate (AcONa; 403.6 mg, 4.920 mmol), I ₂ (499.5 mg, 1.968 mmol) and saturated NaHCO ₃ solution. Universal mixture was confirmed to be basic and stirred at 50 ° C. for 20 minutes. After stirring, Na ₂ S ₂ O ₃ (400.0 mg) was added and the mixture was cooled to room temperature. The reaction mixture was extracted with CHCl ₃ . After washing with a mixed solution of brine and NH ₄ OH aqueous solution, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (700.0 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH = 100: 1: 0.1-30: 1: 0.1) to give EM901 (546.5 mg, 79%) as a white powder. .

EM901

Rf = 0.53 (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 10: 1: 0.2)

HR-MS m / z: 704.4615 [M + H] ⁺ , C ₃₆ H ₆₆ NO ₁₂ Calculated Value: 704.4585 [M + H]

Example  3

Synthesis of de (3'-N-methyl) -3'-N-benzyl-9-dihydro- pseudoerythromycin A 6,9-epoxide (EM902)

To a CHCl ₃ solution (850.0 μl) of EM901 (60.00 mg, 0.0852 mmol) was added diisopropylethylamine (i-Pr ₂ NEt; 74.00 μl, 0.426 mmol) and benzyl bromide (BnBr; 51.00 μl, 0.426 mmol) The mixture was stirred for 1 h at room temperature under Ar atmosphere. After stirring, saturated Na ₂ S ₂ O ₃ solution (10.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated Na ₂ S ₂ O ₃ solution, saturated NH ₄ Cl aqueous solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered and the filtrate was concentrated to yield crude product (70.10 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1) to give EM902 (62.30 mg, 92%) as a white powder.

EM902

HR-MS m / z: 794.5073 [M + H] ⁺ , C ₄₃ H ₇₂ NO ₁₂ Calculated Value: 794.5055 [M + H]

Example  4

Synthesis of Bis-dec (3'-N-methyl) -9-dihydro-pseudoerythromycin A 6,9-epoxide (EM903)

Cool MeOH solution (15.80 mL) of Na (21.80 mg, 0.9480 mmol) to 0 ° C., add EM901 (111.5 mg, 0.1580 mmol) and I ₂ (200.5 mg, 0.7900 mmol), and mix the mixture under 0 atmosphere under Ar atmosphere. Stir at 40 ° C. for 40 minutes. After stirring, Na ₂ S ₂ O ₃ (100.0 mg) was added and the mixture was warmed to room temperature. The reaction mixture was extracted with CHCl ₃ . After washing with a mixed solution of brine and NH ₄ OH aqueous solution, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (100.0 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1-10: 1: 0.1) to give EM903 (98.40 mg, 90%) as a white powder. It was.

EM903

Rf = 0.43 (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 10: 1: 0.2)

HR-MS m / z: 690.4431 [M + H] ⁺ , C ₃₅ H ₆₄ NO ₁₂ Calculation: 690.4429 [M + H]

Example  5

Synthesis of Bis-de (3'-N-methyl) -bis- (3'-N-benzyl) -9-dihydro- pseudoerythromycin A 6,9-epoxide (EM904)

Under Ar atmosphere, EM903 (20.00 mg, 0.0290 mmol) of 1,2-dichloroethane solution (580.0 μl) was cooled to 0 ° C., benzaldehyde (3.100 μl, 0.0300 mmol), AcOH (2.500 μl, 0.0440 mmol) and NaBH (OAc) ₃ (9.300 mg, 0.0440 mmol) was added and the mixture was stirred at 0 ° C. for 2.5 h. After stirring, benzaldehyde (14.80 μl, 0.1430 mmol), AcOH (8.300 μl, 0.1460 mmol) and NaBH (OAc) ₃ (31.00 mg, 0.1460 mmol) were added and the mixture was warmed to room temperature and stirred for 1 hour. After stirring, saturated NaHCO ₃ solution (7.000 mL) was added and the mixture was extracted with CHCl ₃ . Saturated NaHCO ₃ After washing with solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (23.00 mg). The resulting crude product was separated and purified by flash column chromatography to give EM904 (15.80 mg, 63%) as a white powder (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1-50: 1: 0.1) It was.

EM904

HR-MS m / z: 870.5385 [M + H] ⁺ , C ₄₉ H ₇₆ NO ₁₂ Calculated Value: 870.5368 [M + H]

Example  6

Synthesis of de (3'-N-methyl) -3'-N- (p-chlorobenzyl) -9-dihydro- pseudoerythromycin A 6,9-epoxide (EM905)

To a CHCl ₃ solution (280.0 μl) of EM901 (20.00 mg, 0.0280 mmol) was added i-Pr ₂ NEt (24.40 μl, 0.14 mmol) and p-ClBnBr (p-chlorobenzyl bromide: 28.80 mg, 0.1400 mmol), The mixture was stirred at room temperature under N ₂ atmosphere for 2 hours. After stirring, saturated Na ₂ S ₂ O ₃ solution (7.000 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated Na ₂ S ₂ O ₃ solution, saturated NH ₄ Cl solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (24.10 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1) to give EM905 (21.60 mg, 93%) as a white powder.

EM905

Rf = 0.59 (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 30: 1: 0.2)

HR-MS mlz: 828.4657 [M + H] ⁺ , C ₄₃ H ₇₁ NO ₁₂ Cl calcd: 828.4665 [M + H]

Example  7

Synthesis of de [12- (1-hydroxypropyl)]-9-dihydro-12-oxo- pseudoerythromycin A 6,9-epoxide (EM906)

Under N ₂ atmosphere, EM900 (301.4 mg, 0.420 mmol) of CH ₂ Cl ₂ solution (14.00 mL) was cooled to 0 ° C., Pb (OAc) ₄ (300.0 mg, 0.6720 mmol) was added and the mixture was 0 ° C. Stirred for 3 h. After stirring, saturated NaHCO ₃ solution (25.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated NaHCO ₃ solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (305.0 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1-50: 1: 0.1) to give EM906 (154.7 mg, 56%) as a white powder. It was.

EM906

HR-MS m / z: 658.4172 [M + H] ⁺ , C ₃₄ H ₆₀ NO ₁₁ Calculated Value: 658.4166 [M + H]

Example  8

Synthesis of de [12- (1-hydroxypropyl)]-9-dihydro-12-hydroxyoxime- pseudoerythromycin A 6,9-epoxide (EM907)

Under N ₂ atmosphere, EM906 (147.6 mg, 0.2250 mmol) of EtOH solution (1.100 mL) was cooled to 0 ° C., NH ₂ OH.HCl (48.00 mg, 0.6750 mmol) was added and pyridine (1.1 mL, 13.60 mmol) ) Was added dropwise and the mixture was stirred at 0 ° C for 4 h. After stirring, saturated NaHCO ₃ solution (5 mL) was added and the mixture was extracted with CHCl ₃ . The organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to yield crude product (162.0 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 30: 1: 0.1-10: 1: 0.1) to give EM907 (140.4 mg, 93%) as a white powder. It was.

EM907

HR-MS m / z: 673.4256 [M + H] ⁺ , C ₃₄ H ₆₁ N ₂ O ₁₁ Calculated Value: 673.4275 [M + H]

Example  9

Synthesis of de [12- (1-hydroxypropyl)]-9-dihydro- pseudoerythromycin A 6,9-epoxide (EM908)

Under a N ₂ atmosphere, an Me906 solution (3.000 mL) of EM906 (39.00 mg, 0.0593 mmol) was cooled to −78 ° C., NaBH ₄ (22.40 mg, 0.5930 mmol) was added and the mixture was stirred at −78 ° C. for 1.5 h. Stirred. After stirring, the mixture was warmed to room temperature and diluted with CHCl ₃ , brine (30.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with water, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (40.30 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 30: 1: 0.1-10: 1: 0.1) to give EM908 (30.80 mg, 79%) as a white powder. It was.

EM908

HR-MS m / z: 660.4319 [M + H] ⁺ , C ₃₄ H ₆₂ NO ₁₁ Calculation: 660.4323 [M + H]

Example  10

Synthesis of 12,13-epoxy-9-dihydro-pseudoerythromycin A 6,9-epoxide (EM909)

Under N ₂ atmosphere, Martin's sulfate (250.0 mg, 0.3720 mmol) was added to a CH ₂ Cl ₂ solution (1.500 mL) of EM900 (106.8 mg, 0.1490 mmol) and the mixture was stirred for 1.0 h. After stirring, martin sulphate (50.00 mg, 0.0740 mmol) was added and the mixture was stirred for 0.5 h. After stirring, saturated NaHCO ₃ solution (5.000 mL) was added and the mixture was extracted with CHCl ₃ . After washing with brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (110.0 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 40: 1: 0.1-10: 1: 0.1) to give EM909 (34.60 mg, 33%) as a white powder. It was.

EM909

HR-MS m / z: 700.4655 [M + H] ⁺ , C ₃₇ H ₆₆ NO ₁₁ Calculated Value: 700.4636 [M + H]

Example  11

Synthesis of de (3-O-cladinosyl) -9-dihydro-pseudoerythromycin A 6,9-epoxide (EM910)

To a MeOH solution (1.390 mL) of EM900 (100.0 mg, 0.1390 mmol) was added CSA (camposulfonic acid: 48.60 mg, 0.2090 mmol) and the mixture was stirred for 3 hours. After stirring, saturated NaHCO ₃ solution (10.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to yield crude product (99.00 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 50: 1: 0.1-10: 1: 0.1) to give EM910 (18.70 mg, 24%) as a white powder. It was.

EM910

HR-MS m / z: 560.3813 [M + H] ⁺ , C ₂₉ H ₅₄ NO ₉ Calculated Value: 560.3799 [M + H]

Example  12

Synthesis of 4 ", 13-O-diacetyl-9-dihydro-pseudoerythromycin A 6,9-epoxide (EM911)

In a pyridine solution (1.390 mL) of EM900 (100.0 mg, 0.1390 mmol) under N ₂ atmosphere, DMAP (4- (N, N-dimethylamino) pyridine: 1.698 mg, 0.0139 mmol) and Ac ₂ O (78.69 μl, 0.8340) mmol) was added and the mixture was stirred for 1 h. After stirring, DMAP (1.698 mg, 0.0139 mmol) and Ac ₂ O (78.69 μl, 0.8340 mmol) were added and the mixture was stirred for 2 hours. After stirring, 10% citric acid solution (10.00 mL) was added and the mixture was extracted with AcOEt. After washing with saturated NaHCO ₃ solution, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (120.0 mg). The resulting crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 50: 1: 0.1) to give the resulting product (116.0 mg) as a white powder. The resulting product (116.0 mg) of MeOH solution (1.390 mL) was stirred at 50 ° C. for 12 h. After stirring, the solution was concentrated to yield crude product (117.1 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 50: 1: 0.1-10: 1: 0.1) to obtain EM911 (104.5 mg, 94%) as a white powder. Generated.

EM911

HR-MS m / z: 802.4973 [M + H] ⁺ , C ₄₁ H ₇₂ NO ₁₄ Calculated Value: 802.4953 [M + H]

Example  13

Synthesis of Bis-dec (3'-N-methyl) -3'-N-benzyl-9-dihydro- pseudoerythromycin A 6,9-epoxide (EM912)

Under Ar atmosphere, EM903 (20.00 mg, 0.0290 mmol) of 1,2-dichloroethane solution (580.0 μl) was cooled to 0 ° C., benzaldehyde (3.100 μl, 0.0300 mmol), AcOH (2.500 μl, 0.0440 mmol) and NaBH (OAc) ₃ (9.300 mg, 0.0440 mmol) was added and the mixture was stirred at 0 ° C. for 2.5 h. After stirring, benzaldehyde (14.80 μl, 0.1430 mmol), AcOH (8.300 μl, 0.1460 mmol) and NaBH (OAc) ₃ (31.00 mg, 0.1460 mmol) were added and the mixture was warmed to room temperature and stirred for 1 hour. After stirring, saturated NaHCO ₃ Solution (7.000 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated NaHCO ₃ solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (23.00 mg). The resulting crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1-50: 1: 0.1) to give EM912 (6.900 mg, 31%) as a white powder. It was.

EM912

HR-MS m / z: 780.4900 [M + H] ⁺ , C ₄₂ H ₇₀ NO ₁₂ Calculated Value: 780.4898 [M + H]

Example  14

Synthesis of 2′-O-acetyl-9-dihydro-pseudoerythromycin A 6,9-epoxide (EM913)

Under N ₂ atmosphere, Ac ₂ O (506.7 μl, 5.370 mmol) was added to an acetone solution (8.950 mL) of EM900 (641.9 mg, 0.8950 mmol) and the mixture was stirred for 0.5 h. After stirring, saturated NaHCO ₃ solution (100.0 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated NaHCO ₃ solution, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (670.0 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 50: 1: 0.1-20: 1: 0.1) to obtain EM913 (602.3 mg, 89%) as a white powder. Generated.

EM913

HR-MS m / z: 760.4879 [M + H] ⁺ , C ₃₉ H ₇₀ NO ₁₃ Calculated Value: 760.4847 [M + H]

Example  15

Synthesis of de (3'-dimethylamino) -3'-morpholino-9-dihydro-pseudoerythromycin A 6,9-epoxide (EM914)

Under Ar atmosphere, i-Pr ₂ NEt (61.00 μl, 0.3500 mmol) and bis (2-bromoethyl) ether (44.00 μl, 0.3500 mmol) were added to a CH ₃ CN solution (7.000 mL) of EM903 (24.20 mg, 0.0350 mmol). ) Was added and the mixture was stirred at 80 ° C for 20 h. After stirring, i-Pr ₂ NEt (61.00 μl, 0.3500 mmol) and bis (2-bromoethyl) ether (44.00 μl, 0.3500 mmol) were added and the mixture was stirred at 80 ° C. for 6 hours. After stirring, saturated Na ₂ S ₂ O ₃ solution (7.000 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated Na ₂ S ₂ O ₃ solution, saturated NH ₄ Cl solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered and the filtrate was concentrated to give crude product (36.50 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1-30: 1: 0.1) to give EM914 (23.60 mg, 89%) as a white powder. It was.

EM914

Rf = 0.44 (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 30: 1: 0.2)

HR-MS m / z: 760.4885 [M + H] ⁺ , C ₃₉ H ₇₀ NO ₁₃ Calculated Value: 760.4847 [M + H]

Example  16

Synthesis of 2′-O-acetyl-dec (3-O-cladinosyl) -9-dihydro-pseudoerythromycin A 6,9-epoxide (EM915)

To EM913 (104.5 mg, 0.1380 mmol) was added 1.0 N aqueous HCl solution (1.380 mL) and the mixture was stirred for 5 hours. After stirring, saturated NaHCO ₃ Solution (20.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (91.10 mg). The resulting crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 50: 1: 0.1-20: 1: 0.1) to give EM915 (37.60 mg, 46%) as a white powder. It was.

EM915

HR-MS m / z: 602.3899 [M + H] ⁺ , C ₃₁ H ₅₆ NO ₁₀ Calculated Value: 602.3904 [M + H]

Example  17

Synthesis of 2′-O-acetyl-dec (3-O-cladinosyl) -9-dihydro-pseudoerythromycin A 6,9-epoxide 12,13-carbonate (EM916)

Under N ₂ atmosphere, EM915 (32.90 mg, 0.0547 mmol) CH ₂ Cl ₂ solution (1.100 mL) was cooled to −78 ° C., pyridine (79.10 μL, 0.6560 mmol) was added, and triphosphene (32.30 mg, 0.1090 mmol) CH ₂ Cl ₂ The solution (2.200 mL) was added dropwise and the mixture was stirred at -78 ° C for 2 hours. After stirring, pyridine (106.2 μl, 1.312 mmol) was added and the mixture was warmed to room temperature and stirred for 0.5 h. After stirring, saturated NH ₄ Cl solution (15.00 mL) was added and the mixture was extracted with CH ₂ Cl ₂ . After washing with saturated NaHCO ₃ solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to yield crude product (35.00 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 50: 1: 0.1-10: 1: 0.1) to give EM916 (25.00 mg, 73%) as a white powder. It was.

EM916

HR-MS m / z: 628.3697 [M + H] ⁺ , C ₃₂ H ₅₄ NO ₁₁ Calculation: 628.3697 [M + H]

Example  18

Synthesis of 2'-O-acetyl-dec (3-O-cladinosyl) -9-dihydro-3-keto- pseudoerythromycin A 6,9-epoxide 12,13-carbonate (EM917)

Under N ₂ atmosphere, des-martin periodinan (165.8 mg, 0.3910 mmol) was added to a CH ₂ Cl ₂ solution (782.0 μl) of EM916 (24.50 mg, 0.0391 mmol) and the mixture was stirred for 2 hours. After stirring, des-martin periodinan (165.8 mg, 0.3910 mmol) was added and the mixture was stirred for 41 h. After stirring, saturated Na ₂ S ₂ O ₃ solution (15.00 mL) was added and the mixture was extracted with EtOAc. After washing with saturated Na ₂ S ₂ O ₃ solution, saturated NaHCO ₃ solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered and the filtrate was concentrated to give crude product (31.00 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 50: 1: 0.1) to give EM917 (19.50 mg, 80%) as a white powder.

EM917

MS m / z: 626 [M + H] ⁺

Example  19

Synthesis of de (3-O-cladinosyl) -9-dihydro-3-keto- pseudoerythromycin A 6,9-epoxide 12,13-carbonate (EM918)

Me917 solution (225.0 μl) of EM917 (14.10 mg, 0.0225 mmol) was heated to 50 ° C. and the mixture was stirred for 30 h. After stirring, the mixture was concentrated to give crude product (14.20 mg). The resulting crude product was separated and filtered by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 30: 1: 0.1) to give EM918 (12.20 mg, 92%) as a white powder.

EM918

HR-MS m / z: 584.3452 [M + H] ⁺ , C ₃₀ H ₅₀ NO ₁₀ Calculated Value: 584.3435 [M + H]

Example  20

Synthesis of de (3'-N-methyl) -9-dihydro-3'-N- (p-trifluoromethylbenzyl)-pseudoerythromycin A 6,9-epoxide (EM919)

Under N ₂ atmosphere, i-Pr ₂ NEt (45.50 μl, 0.2610 mmol) and p-CF ₃ BnBr (p-trifluoromethylbenzyl bromide) in a CHCl ₃ solution (520.0 μl) of EM901 (36.70 mg, 0.0522 mmol) : 62.40 mg, 0.2610 mmol) was added and the mixture was stirred at rt for 1 h. After stirring, i-Pr ₂ NEt (45.50 μl, 0.2610 mmol) and p-CF ₃ BnBr (62.40 mg, 0.2610 mmol) were added and the mixture was stirred for 2 hours. After stirring, saturated Na ₂ S ₂ O ₃ solution (10.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated Na ₂ S ₂ O ₃ solution, saturated NH ₄ Cl solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (50.00 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1) to yield an EM919 (33.30 mg, 74%) as a white powder.

EM919

HR-MS m / z: 862.4966 [M + H] ⁺ , C ₄₄ H ₇₁ NO ₁₂ F ₃ Calculated Value: 862.4928 [M + H]

Example  21

Synthesis of de (3'-N-methyl) -3'-N- (p-bromobenzyl) -9-dihydro- pseudoerythromycin A 6,9-epoxide (EM920)

Under N ₂ atmosphere, i-Pr ₂ NEt (50.00 μl, 0.2870 mmol) and p-BrBnBr (p-bromobenzyl bromide: 71.70 mg, 0.2870 in EM901 (40.40 mg, 0.0574 mmol) in CHCl ₃ solution (574.0 μl) mmol) was added and the mixture was stirred at rt for 1 h. After stirring, i-Pr ₂ NEt (50.00 μl, 0.2870 mmol) and p-BrBnBr (71.70 mg, 0.2870 mmol) were added and the mixture was stirred at rt for 1 h. After stirring, saturated Na ₂ S ₂ O ₃ solution (50.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated Na ₂ S ₂ O ₃ solution, saturated NH ₄ Cl solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (53.00 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1) to give an EM920 (33.30 mg, 67%) as a white powder.

EM920

HR-MS mlz: 872.4158 [M + H] ⁺ , C ₄₃ H ₇₁ NO ₁₂ Br calc: 872.4160 [M + H]

Example  22

Synthesis of de (3'-N-methyl) -3'-N- (p-fluorobenzyl) -9-dihydro-pseudoerythromycin A 6,9-epoxide (EM921)

Under N ₂ atmosphere, i-Pr ₂ NEt (53.00 μl, 0.3040 mmol) and p-FBnBr (p-fluorobenzyl bromide: 37.90 μl, 0.3040) in a CHCl ₃ solution (607.0 μl) of EM901 (42.70 mg, 0.0607 mmol) mmol) was added and the mixture was stirred at rt for 1 h. After stirring, i-Pr ₂ NEt (53.00 μl, 0.3040 mmol) and p-FBnBr (37.90 μl, 0.3040 mmol) were added and the mixture was stirred at rt for 1.5 h. After stirring, saturated Na ₂ S ₂ O ₃ solution (40.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated Na ₂ S ₂ O ₃ solution, saturated NH ₄ Cl solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to yield crude product (50.00 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1) to give EM921 (42.40 mg, 86%) as a white powder.

EM921

HR-MS m / z: 812.4985 [M + H] ⁺ , C ₄₃ H ₇₁ FNO ₁₂ Calculated Value: 812.4960 [M + H]

Example  23

Synthesis of de (3'-N-methyl) -3'-N- (o-chlorobenzyl) -9-dihydro-pseudoerythromycin A 6,9-epoxide (EM922)

Under N ₂ atmosphere, i-Pr ₂ NEt (77.50 μl, 0.8960 mmol) and o-ClBnBr (104.0 μl, 0.5970 mmol) were added to a CHCl ₃ solution (597.0 μl) of EM901 (42.00 mg, 0.0597 mmol) and the mixture Was stirred at room temperature for 2 hours. After stirring, i-Pr ₂ NEt (38.80 μl, 0.2990 mmol) and o-ClBnBr (52.00 μl, 0.2990 mmol) were added and the mixture was stirred at rt for 0.5 h. After stirring, saturated Na ₂ S ₂ O ₃ solution (40.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated Na ₂ S ₂ O ₃ solution, saturated NH ₄ Cl solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to yield crude product (50.00 mg). The resulting crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1) to give EM922 (48.60 mg, 98%) as a white powder.

EM922

HR-MS m / z: 828.4646 [M + H] ⁺ , C ₄₃ H ₇₁ ClNO ₁₂ Calculated Value: 828.4665 [M + H]

Example  24

Synthesis of de (3'-N-methyl) -3'-N- (m-chlorobenzyl) -9-dihydro- pseudoerythromycin A 6,9-epoxide (EM923)

Under N ₂ atmosphere, i-Pr ₂ NEt (55.20 μl, 0.3170 mmol) and m-ClBnBr (41.60 μl, 0.3170 mmol) were added to a CHCl ₃ solution (634.0 μl) of EM901 (44.60 mg, 0.0634 mmol) and the mixture Was stirred at RT for 1 h. After stirring, i-Pr ₂ NEt (55.20 μl, 0.3170 mmol) and m-ClBnBr (41.60 μl, 0.3170 mmol) were added and the mixture was stirred at room temperature for 2 hours. After stirring, saturated Na ₂ S ₂ O ₃ solution (40.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated Na ₂ S ₂ O ₃ solution, saturated NH ₄ Cl solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to yield crude product (55.00 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1) to give EM923 (45.10 mg, 86%) as a white powder.

EM923

HR-MS m / z: 828.4689 [M + H] ⁺ , C ₄₃ H ₇₁ ClNO ₁₂ Calculated Value: 828.4665 [M + H]

Example  25

Synthesis of de (3'-N-methyl) -9-dihydro-3'-N- (p-iodobenzyl)-pseudoerythromycin A 6,9-epoxide (EM924)

Under N ₂ atmosphere, i-Pr ₂ NEt (50.50 μl, 0.2900 mmol) and p-IBnBr (p-iobenzyl bromide: 86.10 mg, 0.2900 mmol) in CHCl ₃ solution (580.0 μl) of EM901 (40.80 mg, 0.0580 mmol) ) Was added and the mixture was stirred at rt for 1 h. After stirring, i-Pr ₂ NEt (50.50 μl, 0.2900 mmol) and p-IBnBr (86.10 mg, 0.2900 mmol) were added and the mixture was stirred at rt for 2 h. After stirring, saturated Na ₂ S ₂ O ₃ solution (40.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated Na ₂ S ₂ O ₃ solution, saturated NH ₄ Cl solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to yield crude product (55.00 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1) to give EM924 (48.20 mg, 90%) as a white powder.

EM924

HR-MS m / z: 920.4011 [M + H] ⁺ , C ₄₃ H ₇₁ NO ₁₂ I calculated: 920.4021 [M + H]

Example  26

De (3'-N-methyl) -3'-N- (p-chlorobenzyl) -de (3-O-cladinosyl) -9-dihydro-pseudoerythromycin A 6,9-epoxide (EM925 ) Synthesis

Under N ₂ atmosphere, i-Pr ₂ NEt (120.0 μl, 0.6890 mmol) and p-ClBnBr (141.6 mg, 0.6890) were added to a CHCl ₃ solution (689.0 μl) of EM934 (37.60 mg, 0.0689 mmol) obtained in Example 35 below. mmol) was added and the mixture was stirred at rt for 2 h. After stirring, saturated Na ₂ S ₂ O ₃ solution (40.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated Na ₂ S ₂ O ₃ solution, saturated NH ₄ Cl solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to yield crude product (50.00 mg). The resulting crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1) to give EM925 (33.00 mg, 72%) as a white powder.

EM925

HR-MS m / z: 670.3705 [M + H] ⁺ , C ₃₅ H ₅₇ ClNO ₉ Calculated Value: 670.3722 [M + H]

Example  27

Synthesis of de (3-O-cladinosyl) -de (3'-dimethylamino) -3'-morpholino-9-dihydro- pseudoerythromycin A 6,9-epoxide (EM926)

To a CH ₃ CN solution (937.0 μl) of EM914 (71.20 mg, 0.0937 mmol) was added 1.0 N aqueous HCl solution (937.0 μl) and the mixture was stirred for 0.5 h. After stirring, saturated NaHCO ₃ solution (50.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to yield crude product (60.00 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 50: 1: 0.1-30: 1: 0.1) to give EM926 (25.30 mg, 44%) as a white powder. It was.

EM926

HR-MS m / z: 602.3884 [M + H] ⁺ , C ₃₁ H ₅₆ NO ₁₀ Calculated Value: 602.3904 [M + H]

Example  28

Synthesis of 2'-O- (p-bromobenzoyl) -9-dihydro-pseudoerythromycin A 6,9-epoxide (EM927)

Under N ₂ atmosphere, Et ₃ N (58.30 μl, 0.4200 mmol) and p-BrBzCl (p-bromobenzoyl chloride: 30.70 mg, 0.1400 mmol) in a CH ₃ CN solution (4.200 mL) of EM900 (100.8 mg, 0.1400 mmol) ) Was added and the mixture was stirred for 1.0 h. After stirring, aqueous NH ₃ solution (6.000 mL) was added and the mixture was concentrated to give crude product (126.0 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 50: 1: 0.1-30: 1: 0.1) to give EM927 (107.4 mg, 85%) as a white powder. It was.

EM927

HR-MS mlz: 900.4091 [M + H] ⁺ , C ₄₄ H ₇₁ NO ₁₃ Br calc: 900.4109 [M + H]

Example  29

Synthesis of Bis-dec (3'-N-methyl) -3'-N- (p-chlorobenzyl) -9-dihydro- pseudoerythromycin A 6,9-epoxide (EM928)

Under N ₂ atmosphere, EM903 (49.60 mg, 0.0719 mmol) of 1,2-dichloroethane solution (1.440 mL) was cooled to 0 ° C., p-chlorobenzaldehyde (10.60 mg, 0.0755 mmol), AcOH (6.180 μl, 0.1080 mmol) and NaBH (OAc) ₃ (22.90 mg, 0.1080 mmol) were added and the mixture was stirred at 0 ° C. for 2.5 h, warmed to rt and stirred for 1 h. After stirring, saturated NaHCO ₃ solution (50.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated NaHCO ₃ solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (62.00 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1-10: 1: 0.1) to give EM928 (32.30 mg, 55%) as a white powder. It was.

EM928

HR-MS m / z: 814.4515 [M + H] ⁺ , C ₄₂ H ₆₉ ClNO ₁₂ Calculated Value: 814.4508 [M + H]

Example  30

Synthesis of de (3'-N-methyl) -3'-N-propargyl-9-dihydro- pseudoerythromycin A 6,9-epoxide (EM929)

To a MeOH solution (12.67 mL) of EM900 (909.3 mg, 1.267 mmol) was added AcONa (519.7 mg, 6.335 mmol), I ₂ (643.2 mg, 2.534 mmol) and saturated NaHCO ₃ solution. Confirmed, and stirred at 50 ° C. for 20 minutes. After stirring, Na ₂ S ₂ O ₃ (400.0 mg) was added and the mixture was cooled to room temperature. The reaction mixture was extracted with CHCl ₃ . After washing with a mixed solution of brine and NH ₄ OH, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give the crude product. Under a N ₂ atmosphere, a crude product (892.0 mg, 1.267 mmol) of CHCl ₃ solution (12.67 mL) obtained with i-Pr ₂ NEt (1.100 mL, 6.335 mmol) and 3-bromopropine (471.9 μL, 6.335 mmol). Was added and the mixture was stirred at rt for 1 h. After stirring, i-Pr ₂ NEt (1.100 mL, 6.335 mmol) and 3-bromopropine (471.9 μl, 6.335 mmol) were added and the mixture was stirred at rt for 12 h. After stirring, saturated Na ₂ S ₂ O ₃ solution (200.0 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated Na ₂ S ₂ O ₃ solution, saturated NH ₄ Cl solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (940.2 mg). The resulting crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1) to give EM929 (600.1 mg, 64%) as a white powder.

EM929

HR-MS m / z: 742.4730 [M + H] ⁺ , C ₃₉ H ₆₈ NO ₁₂ Calculated Value: 742.4742 [M + H]

Example  31

Synthesis of de (3'-N-methyl) -2'-O-3'-N-bis (benzyloxycarbonyl) -9-dihydro-pseudoerythromycin A 6,9-epoxide (EM930)

To NH900 (5.004 g, 6.975 mmol) EtOAc solution (69.80 mL) was added NaHCO ₃ (8.790 g, 104.6 mmol), CbzCl (benzyloxycarbonyl chloride: 14.93 mL, 104.6 mmol) was added dropwise and the mixture was 70 Heat to C and stir for 2 h. After stirring, Et ₃ N was added and the mixture was cooled to room temperature. The reaction mixture was extracted with EtOAc. After washing with brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (7.000 g). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 50: 1: 0.1) to give an EM930 (6.365 g, 94%) as a white powder.

EM930

HR-MS m / z: 994.5170 [M + Na] ⁺ , C ₅₂ H ₇₇ NO ₁₆ Na calcd: 994.5140 [M + Na]

Example  32

De (3'-N-methyl) -2'-O-3'-N-bis (benzyloxycarbonyl) -de (3-O-cladinosyl) -9-dihydro- pseudoerythromycin A 6, Synthesis of 9-epoxide (EM931)

To a solution of 1.0 N HCl (52.30 mL) was added to an EM930 (5.081 g, 5.230 mmol) CH ₃ CN solution (104.6 mL), and the mixture was stirred for 4 h. After stirring, saturated NaHCO ₃ solution (400.0 mL) was added and the mixture was extracted with CHCl ₃ . After washing with brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (4.312 g). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 50: 1: 0.1) to give EM931 (4.028 g, 95%) as a white powder.

EM931

HR-MS m / z: 814.4384 [M + H] ⁺ , C ₄₄ H ₆₄ NO ₁₃ Calculation: 814.4378 [M + H]

Example  33

2'-O-acetyl-de (3-O-cladinosyl) -9-dihydro-3-keto-de (3'-dimethylamino) -3'-morpholino- pseudoerythromycin A 6,9 Synthesis of Epoxide 12,13-carbonate (EM932)

To a CH ₂ Cl ₂ solution (4.560 mL) of EM948 (152.5 mg, 0.228 mmol) obtained in Example 48 below under N ₂ atmosphere, des-martin periodinan (165.8 mg, 0.391 mmol) was added and the mixture was Stir for 2 hours. After stirring, saturated Na ₂ S ₂ O ₃ solution (50.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated Na ₂ S ₂ O ₃ solution, saturated NaHCO ₃ solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (160.0 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1) to give EM932 (151.1 mg, 90%) as a white powder.

EM932

HR-MS m / z: 668.3642 [M + H] ⁺ , C ₃₄ H ₅₄ NO ₁₂ Calculation: 668.3646 [M + H]

Example  34

Synthesis of de (3'-N-methyl) -3'-N-ethyl-9-dihydro- pseudoerythromycin A 6,9-epoxide (EM933)

Under N ₂ atmosphere, i-Pr ₂ NEt (102.1 μl, 0.5860 mmol) and bromoethane (43.70 μl, 0.5860 mmol) were added to a CH ₃ CN solution (586.0 μl) of EM901 (41.20 mg, 0.0586 mmol), The mixture was stirred at rt for 22 h. After stirring, the mixture was heated to 50 ° C. and stirred for 134 hours. In addition, i-Pr ₂ NEt (102.1 μl, 0.5860 mmol) and bromoethane (43.70 μl, 0.5860 mmol) were added and the mixture was stirred at 50 ° C. for 14 hours. After stirring, saturated Na ₂ S ₂ O ₃ solution (40.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated Na ₂ S ₂ O ₃ solution, saturated NH ₄ Cl solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to yield crude product (50.00 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1) to give EM933 (42.40 mg, 86%) as a white powder.

EM933

HR-MS m / z: 732.4911 [M + H] ⁺ , C ₃₈ H ₇₀ NO ₁₂ Calculated Value: 732.4898 [M + H]

Example  35

Synthesis of de (3-O-cladinosyl) -de (3'-N-methyl) -9-dihydro-pseudoerythromycin A 6,9-epoxide (EM934)

N ₂ Under air, Pd (OH) ₂ (21.70 mg) and EtOH (2.660 mL) were added to EM931 (108.4 mg, 0.1330 mmol) and the mixture was stirred for 1 h at room temperature under H ₂ atmosphere. After stirring, the mixture was filtered and the filtrate was concentrated to give crude product (150.1 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 30: 1: 0.1-10: 1: 0.1) to give EM934 (70.30 mg, 97%) as a white powder. It was.

EM934

HR-MS m / z: 546.3622 [M + H] ⁺ , C ₂₈ H ₅₄ NO ₉ Calculation: 546.3642 [M + H]

Example  36

De (3-O-cladinosyl) -9-dihydro-3-keto-de (3'-dimethylamino) -3'-morpholino- pseudoerythromycin A 6,9-epoxide 12,13- Synthesis of Carbonate (EM935)

EM932 (104.6 mg, 0.157 mmol) of MeOH solution (6.280 mL) was heated to 50 ° C. and stirred for 68 h. After stirring, the mixture was concentrated to give crude product (101.2 mg). The resulting crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1) to give EM935 (98.00 mg, 100%) as a white powder.

EM935

HR-MS m / z: 626.3533 [M + H] ⁺ , C ₃₂ H ₅₂ NO ₁₁ Calculated Value: 626.3540 [M + H]

Example  37

De (3'-N-methyl) -2'-O-3'-N-bis (benzyloxycarbonyl) -de (3-O-cladinosyl) -9-dihydro- pseudoerythromycin A 6, Synthesis of 9-epoxide 12,13-carbonate (EM936)

Under N ₂ atmosphere, a solution of CH ₂ Cl ₂ (49.80 mL) of EM931 (2.027 g, 2.492 mmol) was cooled to −78 ° C., pyridine (2.420 mL, 29.90 mmol) was added, and triphosphene (1.479 g, 4.984 mmol) of CH ₂ Cl ₂ solution (99.70 mL) was added dropwise, and the mixture was warmed from −78 ° C. to room temperature and stirred for 0.5 h. After stirring, saturated NH ₄ Cl solution (400.0 mL) was added and the mixture was extracted with CH ₂ Cl ₂ . After washing with saturated NaHCO ₃ solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (1.900 g). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1) to give EM936 (1.882 g, 90%) as a white powder.

EM936

HR-MS mlz: 862.4000 [M + Na] ⁺ , C ₄₅ H ₆₁ NO ₁₄ Na calcd: 862.3990 [M + Na]

Example  38

De (3'-N-methyl) -2'-O-3'-N-bis (benzyloxycarbonyl) -de (3-O-cladinosyl) -9-dihydro-3-keto- pseudoerythro Synthesis of Mycin A 6,9-epoxide 12,13-carbonate (EM937)

Under N ₂ atmosphere, des-martin periodinan (4.343 g, 10.24 mmol) was added to a CH ₂ Cl ₂ solution (40.80 mL) of EM936 (1.718 g, 2.047 mmol) and the mixture was stirred for 1.5 h. After stirring, saturated Na ₂ S ₂ O ₃ solution (300.0 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated Na ₂ S ₂ O ₃ solution, NaHCO ₃ solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (1.700 g). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 50: 1: 0.1) to give EM937 (1.668 g, 97%) as a white powder.

EM937

HR-MS m / z: 838.4012 [M + H] ⁺ , C ₄₅ H ₆₀ NO ₁₄ Calculation: 838.4014 [M + H]

Example  39

De (3-O-cladinosyl) -9-dihydro-3-keto-de (3'-N-methyl)-pseudoerythromycin A 6,9-epoxide 12,13-carbonate (EM938) Synthesis of

Under N ₂ atmosphere, Pd (OH) ₂ (292.2 mg) and EtOH (34.90 mL) were added to EM937 (1.461 g, 1.745 mmol) and the mixture was stirred for 3 h at room temperature under H ₂ atmosphere. After stirring, Pd (OH) ₂ solution (292.2 mg) was added under N ₂ atmosphere and the mixture was stirred for 2.5 h at room temperature under H ₂ atmosphere. In addition, after stirring, N ₂ Pd (OH) ₂ (146.1 mg) was added under air and the mixture was stirred for 1 h at room temperature under H ₂ atmosphere. The mixture was filtered and the filtrate was concentrated to give crude product (1.302 g). The resulting crude product was isolated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 50: 1: 0.1-30: 1: 0.1) to give EM938 (967.3 mg, 97%) as a white powder. It was.

EM938

HR-MS m / z: 570.3307 [M + H] ⁺ , C ₂₉ H ₄₈ NO ₁₀ Calculated Value: 570.3278 [M + H]

Example  40

De (3'-N-methyl) -3'-N- (p-chlorobenzyl) -de (3-O-cladinosyl) -9-dihydro-3-keto- pseudoerythromycin A 6,9- Synthesis of Epoxide 12,13-carbonate (EM939)

I-Pr ₂ NEt (928.4 μl, 5.330 mmol) and p-ClBnBr (1.095 g, 5.330 mmol) were added to an EM938 (303.4 mg, 0.533 mmol) CHCl ₃ solution (5.330 mL), and the mixture was N _2. Stir at room temperature for 2 hours under air. After stirring, saturated Na ₂ S ₂ O ₃ solution (50.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated Na ₂ S ₂ O ₃ solution, saturated NH ₄ Cl solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (350.1 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1) to give EM939 (342.5 mg, 93%) as a white powder.

EM939

HR-MS mlz: 694.3353 [M + H] ⁺ , C ₃₆ H ₅₃ NO ₁₀ Cl calcd: 694.3358 [M + H]

Example  41

Synthesis of 9-dihydro-de (3'-N-methyl) -3'-N-i-propyl- pseudoerythromycin A 6,9-epoxide (EM940)

Under N ₂ atmosphere, i-Pr ₂ NEt (98.20 μl, 0.5840 mmol) and i-PrI (2-iodine propane: 56.30 μl, 0.5640 mmol) in a CH ₃ CN solution (564.0 μl) of EM901 (39.70 mg, 0.0564 mmol) ) Was added and the mixture was stirred at 50 ° C. for 134 h. After stirring, i-Pr ₂ NEt (98.20 μl, 0.5840 mmol) and i-PrI (56.30 μl, 0.5640 mmol) were added and the mixture was stirred at 50 ° C. for 26.5 h. In addition, i-Pr ₂ NEt (196.4 μl, 1.128 mmol) and i-PrI (112.6 μl, 1.128 mmol) were added and the mixture was stirred at 50 ° C. for 97.5 h. After stirring, saturated Na ₂ S ₂ O ₃ solution (30.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated Na ₂ S ₂ O ₃ solution, saturated NH ₄ Cl solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to yield crude product (50.00 mg). The resulting crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1-50: 1: 0.1) to give EM940 (16.10 mg, 38%) as a white powder. It was.

EM940

HR-MS mlz: 746.5043 [M + H] ⁺ , C ₃₉ H ₇₂ NO ₁₂ calc: 746.5055 [M + H]

Example  42

Synthesis of de (3-O-cladinosyl) -9-dihydro-bis-de (3'-N-methyl)-pseudoerythromycin A 6,9-epoxide (EM941)

Cool a solution of NaOH (222.2 mg, 9.666 mmol) (161.1 mL) to 0 ° C. and add N934 (878.6 mg, 1.611 mmol) and I ₂ (2.044 g, 8.055 mmol) under N ₂ atmosphere and mix Was stirred at 0 ° C. for 1 h. After stirring, Na ₂ S ₂ O ₃ (6.000 g) was added and the mixture was warmed to room temperature. The reaction mixture was extracted with CHCl ₃ . After washing with a mixed solution of brine and NH ₄ OH, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (870.2 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 30: 1: 0.1-10: 1: 0.1) to give EM941 (549.7 mg, 64%) as a white powder. It was.

EM941

HR-MS m / z: 532.3509 [M + H] ⁺ , C ₂₇ H ₅₀ NO ₉ Calculated Value: 532.3486 [M + H]

Example  43

De (3'-N-methyl) -2'-O-3'-N-bis (benzyloxycarbonyl) -de (3-O-cladinosyl) -9-dihydro- pseudoerythromycin A 6, Synthesis of 9-epoxide 12,13-isopropylidene acetal (EM942)

EMTS 1 (686.5 mg, 0.843 mmol) in DMF (dimethylformamide) solution (8.434 mL) in PPTS (pyridinium p-toluenesulfonate: 2.120 g, 8.434 mmol), Me ₂ C (OMe) ₂ (acetone dimethyl acetal: 5.497 mL, 44.70 mmol) was added and the mixture was stirred for 21 h at rt under N ₂ atmosphere. After stirring, saturated NaHCO ₃ solution (100.0 mL) was added and the mixture was extracted with CHCl ₃ . After washing with H ₂ O, the organic layer was dried over Na ₂ SO ₄ , the residue was filtered and the filtrate was concentrated. The concentrate was dissolved in hexanes: AcOEt = 1: 1 and the solution was washed with H ₂ O. The organic layer was dried over Na ₂ SO ₄ . The residue was filtered and the filtrate was concentrated to yield crude product (700.2 mg). The resulting crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1) to give EM942 (697.6 mg, 97%) as a white powder.

EM942

HR-MS m / z: 876.4503 [M + Na] ⁺ , C ₄₇ H ₆₇ NO ₁₃ Na calcd: 876.4510 [M + Na]

Example  44

De (3'-N-methyl) -2'-O-3'-N-bis (benzyloxycarbonyl) -de (3-O-cladinosyl) -9-dihydro-3-keto- pseudoerythro Synthesis of Mycin A 6,9-epoxide 12,13-isopropylidene acetal (EM943)

Des-Martin periodinan (479.3 mg, 1.130 mmol) was added to a solution of EM942 (482.6 mg, 0.565 mmol) CH ₂ Cl ₂ (11.30 mL) and the mixture was stirred for 2 hours. After stirring, saturated Na ₂ S ₂ O ₃ solution (100.0 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated Na ₂ S ₂ O ₃ solution, saturated NaHCO ₃ solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (1.700 g). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1) to give EM943 (480.0 mg, 100%) as a white powder.

EM943

HR-MS mlz: 874.4383 [M + Na] ⁺ , C ₄₇ H ₆₅ NO ₁₃ Na calc .: 874.4354 [M + Na].

Example  45

De (3-O-cladinosyl) -9-dihydro-3-keto-de (3'-N-methyl)-pseudoerythromycin A 6,9-epoxide 12,13-isopropylidene acetal (EM944 ) Synthesis

Under N ₂ atmosphere, Pd (OH) ₂ (81.4 mg) and EtOH (9.56 mL) were added to EM943 (406.8 mg, 0.478 mmol) and the mixture was stirred for 2 h at room temperature under H ₂ atmosphere. The mixture was filtered and the filtrate was concentrated to yield crude product (300.0 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 50: 1: 0.1-10: 1: 0.1) to give EM944 (275.6 mg, 99%) as a white powder. It was.

EM944

HR-MS m / z: 584.3795 [M + H] ⁺ , C ₃₁ H ₅₄ NO ₉ Calculation: 584.3799 [M + H]

Example  46

De (3-O-cladinosyl) -9-dihydro-de (3'-dimethylamino) -3'-morpholino- pseudoerythromycin A 6,9-epoxide 12,13-carbonate ( Synthesis of EM946)

Under N ₂ atmosphere, EM926 (259.3 mg, 0.431 mmol) of CH ₂ Cl ₂ solution (8.620 mL) was cooled to −78 ° C., pyridine (418.3 μl, 5.172 mmol) was added, and triphosphene (255.8 mg, 0.862 mmol) of CH ₂ Cl ₂ solution (17.24 mL) was added dropwise, and the mixture was warmed from −78 ° C. to room temperature and stirred for 1 hour. After stirring, saturated NH ₄ Cl solution (100.0 mL) was added and the mixture was extracted with CH ₂ Cl ₂ . After washing with saturated NaHCO ₃ solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (285.3 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1-50: 1: 0.1) to give EM946 (265.7 mg, 98%) as a white powder. It was.

EM946

HR-MS m / z: 628.3669 [M + H] ⁺ , C ₃₂ H ₅₄ NO ₁₁ Calculation: 628.3697 [M + H]

Example  47

De (3'-N-methyl) -3'-N- (p-chlorobenzyl) -de (3-O-cladinosyl) -9-dihydro-3-keto-pseudorithromycin A 6,9 Synthesis of Epoxide 12,13-Isopropylidene Acetal (EM947)

To a solution of CH94 ₃ (30.9 960) of EM943 (230.9 mg, 0.396 mmol), i-Pr2NEt (689.8 μl, 3.960 mmol) and p-ClBnBr (813.7 mg, 3.960 mmol) were added and the mixture was stirred at room temperature under N ₂ atmosphere. Stir for 2 hours. After stirring, saturated Na ₂ S ₂ O ₃ solution (30.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated Na ₂ S ₂ O ₃ solution, saturated NH ₄ Cl solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (279.1 mg). The obtained crude product was isolated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1-50: 1: 0.1) to give EM947 (250.0 mg, 89%) as a white powder. It was.

EM947

HR-MS mlz: 708.3847 [M + H] ⁺ , C ₃₈ H ₅₉ NO ₉ Cl calcd: 708.3878 [M + H]

Example  48

2'-O-acetyl-de (3-O-cladinosyl) -9-dihydro-de (3'-dimethylamino) -3'-morpholino- pseudoerythromycin A 6,9-epoxide 12 Synthesis of, 13-carbonate (EM948)

Under N ₂ atmosphere, Ac ₂ O (189.0 μl, 2.004 mmol) was added to an acetone solution (3.340 mL) of EM946 (209.7 mg, 0.334 mmol) and the mixture was stirred for 2 h. Further, after stirring, Ac ₂ O (189.0 μl, 2.004 mmol) was added and the mixture was stirred for 4 hours. After stirring, saturated NaHCO ₃ solution (100.0 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated NaHCO ₃ solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (210.1 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 50: 1: 0.1) to give EM948 (202.9 mg, 91%) as a white powder.

HR-MS m / z: 670.3809 [M + H] ⁺ , C ₃₄ H ₅₆ NO ₁₂ Calculated Value: 670.3803 [M + H]

Example  49

De (3'-N-methyl) -3'-N- (p-chlorobenzyl) -de (3-O-cladinosyl) -9-dihydro-3-keto- pseudoerythromycin A 6,9- Synthesis of Epoxide (EM949)

Under N ₂ atmosphere, TsOH (p-toluenesulfonic acid: 41.30 mg, 0.217 mmol) was added to a solution of TH94 (tetrahydrofuran) of EM947 (75.3 mg, 0.106 mmol) in THF (tetrahydrofuran) and the mixture was stirred for 1 hour. . After stirring, TsOH (41.30 mg, 0.217 mmol) was added and the mixture was stirred for 4 hours. In addition, TsOH (201.4 mg, 1.059 mmol) was added and the mixture was stirred for 12 hours. After stirring, saturated NaHCO ₃ solution (20.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (80.12 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1) to give EM949 (43.2 mg, 61%) as a white powder.

EM949

HR-MS mlz: 690.3353 [M + Na] ⁺ , C ₃₅ H ₅₄ NO ₉ ClNa calc: 690.3385 [M + Na]

Example  50

De (3-O-cladinosyl) -9-dihydro-de (3'-dimethylamino) -3'-morpholino- pseudoerythromycin A 6,9-epoxide 12,13-isopropylidene acetal Synthesis of (EM950)

To a solution of EM926 (235.3 mg, 0.391 mmol) in DMF (3.910 mL) was added PPTS (982.0 mg, 3.910 mmol) and Me ₂ C (OME) ₂ (2.550 mL, 20.72 mmol) and the mixture was allowed to come to room temperature under N ₂ atmosphere. Stirred for 5 hours. After stirring, saturated NaHCO ₃ solution (30.00 mL) was added and the mixture was extracted with CHCl ₃ . The organic layer was dried over Na ₂ SO ₄ , the residue was filtered and the filtrate was concentrated. The concentrate was dissolved in hexanes: AcOEt = 1: 1 and the solution was washed with H ₂ O. The organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (250.2 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1-50: 1: 0.1) to give EM950 (236.6 mg, 94%) as a white powder. It was.

EM950

HR-MS m / z: 642.4221 [M + H] ⁺ , C ₃₄ H ₆₀ NO ₁₀ Calculated Value: 642.4217 [M + Na]

Example  51

2'-O-acetyl-de (3-O-cladinosyl) -9-dihydro-de (3'-dimethylamino) -3'-morpholino- pseudoerythromycin A 6,9-epoxide 12 Synthesis of 13-isopropylidene acetal (EM951)

Under an N ₂ atmosphere, Ac ₂ O (79.80 μl, 0.846 mmol) was added to an acetone solution (2.820 mL) of EM950 (181.1 mg, 0.282 mmol) and the mixture was stirred for 2 hours. In addition, Ac ₂ O (425.6 μl, 4.512 mmol) was added and the mixture was stirred for 1 h. After stirring, saturated NaHCO ₃ solution (25.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (210.1 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 50: 1: 0.1) to give EM951 (192.0 mg, 100%) as a white powder.

EM951

HR-MS m / z: 684.4318 [M + H] ⁺ , C ₃₆ H ₆₂ NO ₁₁ Calculated Value: 684.4323 [M + H]

Example  52

2'-O-acetyl-de (3-O-cladinosyl) -9-dihydro-3-keto-de (3'-dimethylamino) -3'-morpholino- pseudoerythromycin A 6,9 Synthesis of Epoxide 12,13-Isopropylidene Acetal (EM952)

Under N ₂ atmosphere, des-martin periodinan (164.4 mg, 0.388 mmol) was added to a CH ₂ Cl ₂ solution (3.900 mL) of EM951 (132.3 mg, 0.194 mmol) and the mixture was stirred for 1 h. After stirring, saturated Na ₂ S ₂ O ₃ solution (25.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated Na ₂ S ₂ O ₃ solution, saturated NaHCO ₃ solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (151.0 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1-50: 1: 0.1) to give EM952 (121.6 mg, 92%) as a white powder. It was.

EM952

HR-MS m / z: 682.4163 [M + H] ⁺ , C ₃₆ H ₆₀ NO ₁₁ Calculated Value: 682.4166 [M + H]

Example  53

De (3-O-cladinosyl) -9-dihydro-3-keto-de (3'-dimethylamino) -3'-morpholino- pseudoerythromycin A 6,9-epoxide 12,13- Synthesis of Isopropylidene Acetal (EM953)

MeOH solution (5.440 mL) of EM952 (92.4 mg, 0.136 mmol) was heated to 50 ° C. and stirred for 36 h. After stirring, the solution was concentrated to give crude product (101.2 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1-50: 1: 0.1) to give EM953 (85.50 mg, 98%) as a white powder. It was.

EM953

HR-MS m / z: 640.4053 [M + H] ⁺ , C ₃₄ H ₅₈ NO ₁₀ Calculated Value: 640.4061 [M + H]

Example  54

Of de (3-O-cladinosyl) -9-dihydro-3-keto-de (3'-dimethylamino) -3'-morpholino- pseudoerythromycin A 6,9-epoxide (EM954) synthesis

To a mixed solution of EM953 (56.6 mg, 0.0885 mmol) of THF and H ₂ O (4: 1) (1.770 mL) under N ₂ atmosphere, add TsOH (33.70 mg, 0.177 mmol) and stir the mixture for 28 h. It was. After stirring, saturated NaHCO ₃ solution (10.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (60.12 mg). The resulting crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 50: 1: 0.1) to give EM954 (44.9 mg, 85%) as a white powder.

EM954

HR-MS m / z: 600.3749 [M + H] ⁺ , C ₃₁ H ₅₄ NO ₁₀ Calculated Value: 600.3748 [M + Na]

Example  55

Synthesis of de (3'-dimethylamino) -3'-piperidino-9-dihydro-pseudoerythromycin A 6,9-epoxide (EM955)

Under N ₂ atmosphere, i-Pr ₂ NEt (554.0 μl, 3.180 mmol) and 1,5-dibromopentane (433.0 μl, 3.180 mmol) were added to a CH ₃ CN solution (31.80 mL) of EM903 (109.5 mg, 0.159 mmol). ) Was added and the mixture was stirred at 80 ° C for 0.5 h. After stirring, i-Pr ₂ NEt (1.300 mL, 9.540 mmol) and 1,5-dibromopentane (1.660 mL, 9.540 mmol) were added and the mixture was stirred at 80 ° C. for 21 h. After stirring, saturated Na ₂ S ₂ O ₃ solution (100.0 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated Na ₂ S ₂ O ₃ solution, saturated NH ₄ Cl solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (102.7 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 50: 1: 0.1) to give EM955 (98.20 mg, 82%) as a white powder.

EM955

HR-MS m / z: 758.5054 [M + H] ⁺ , C ₄₀ H ₇₂ NO ₁₂ Calculation: 758.5055 [M + H]

Example  56

Synthesis of de (3'-dimethylamino) -3'-pyrrolidino-9-dihydro- pseudoerythromycin A 6,9-epoxide (EM956)

Under N ₂ atmosphere, i-Pr ₂ NEt (571.3 μl, 3.280 mmol) and 1,4-dibromobutane (388.7 μl, 3.280 mmol) were added to a CH ₃ CN solution (32.80 mL) of EM903 (112.9 mg, 0.164 mmol). ) Was added and the mixture was stirred at 80 ° C for 2 h. After stirring, i-Pr ₂ NEt (1.710 mL, 9.840 mmol) and 1,4-dibromobutane (1.170 mL, 9.840 mmol) were added and the mixture was stirred at 80 ° C. for 22 h. After stirring, saturated Na ₂ S ₂ O ₃ solution (100.0 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated Na ₂ S ₂ O ₃ solution, saturated NH ₄ Cl solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered and the filtrate was concentrated to give crude product (100.7 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 50: 1: 0.1-30: 1: 0.1) to give EM956 (75.10 mg, 62%) as a white powder. It was.

EM956

HR-MS m / z: 744.4893 [M + H] ⁺ , C ₃₉ H ₇₀ NO ₁₂ Calculated Value: 744.4898 [M + H]

Example  57

Synthesis of de (3'-N-methyl) -3'-N-allyl-9-dihydro- pseudoerythromycin A 6,9-epoxide (EM957)

Under N ₂ atmosphere, i-Pr ₂ NEt (263.0 μl, 1.510 mmol) and allyl iodine (137.1 μl, 1.510 mmol) were added to a CHCl ₃ solution (1.510 mL) of EM901 (106.4 mg, 0.151 mmol) and the mixture was Stir for 3 hours. After stirring, i-Pr ₂ NEt (263.0 μl, 1.510 mmol) and allyl iodine (137.1 μl, 1.510 mmol) were added and the mixture was stirred for 3 hours. After stirring, saturated Na ₂ S ₂ O ₃ solution (100.0 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated Na ₂ S ₂ O ₃ solution, saturated NH ₄ Cl solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (80.50 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 50: 1: 0.1-30: 1: 0.1) to give EM957 (60.50 mg, 54%) as a white powder. It was.

EM957

HR-MS m / z: 744.4911 [M + H] ⁺ , C ₃₉ H ₇₀ NO ₁₂ Calculated Value: 744.4898 [M + H]

Example  58

Synthesis of de (3'-N-methyl) -9-dihydro-3'-N- (p-methylbenzyl)-pseudoerythromycin A 6,9-epoxide (EM958)

Under N ₂ atmosphere, i-Pr ₂ NEt (263.9 μl, 1.360 mmol) and p-MeBnCl (178.7 μl, 1.360 mmol) were added to a CHCl ₃ solution (680.0 μl) of EM901 (47.80 mg, 0.0680 mmol) and the mixture Was stirred at RT for 0.5 h. After stirring, NaI (203.9 mg, 1.360 mmol) was added and the mixture was stirred at rt for 22 h. After stirring, saturated Na ₂ S ₂ O ₃ solution (15.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated Na ₂ S ₂ O ₃ solution, saturated NH ₄ Cl solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (40.30 mg). The resulting crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1) to give EM958 (24.20 mg, 45%) as a white powder.

EM958

HR-MS m / z: 808.5217 [M + H] ⁺ , C ₄₄ H ₇₄ NO ₁₂ Calculated Value: 808.5211 [M + H]

Example  59

Synthesis of de (3'-N-methyl) -9-dihydro-3'-N- (p-methoxybenzyl)-pseudoerythromycin A 6,9-epoxide (EM959)

Under N ₂ atmosphere, EM901 (112.1 mg, 0.159 mmol) of 1,2-dichloroethane solution (3.180 mL) was cooled to 0 ° C., p-anisaldehyde (39.50 μl, 0.326 mmol), AcOH (27.30 μl, 0.477 mmol) and NaBH (OAc) ₃ (101.1 mg, 0.477 mmol) were added and the mixture was warmed to room temperature and stirred for 2.5 h. After stirring, saturated NaHCO ₃ solution (20.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated NaHCO ₃ solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to yield crude product (100.00 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 100: 1: 0.1-10: 1: 0.1) to give EM959 (63.40 mg, 48%) as a white powder. It was.

EM959

HR-MS m / z: 824.5173 [M + H] ⁺ , C ₄₄ H ₇₄ NO ₁₃ Calculated Value: 824.5160 [M + H]

Example  60

Synthesis of de (3'-N-methyl) -9-dihydro-3'-N-acetyl- pseudoerythromycin A 6,9-epoxide (EM960)

Under a N ₂ atmosphere, a solution of CH ₂ Cl ₂ (3.540 mL) of EM901 (124.9 mg, 0.177 mmol) is cooled to 0 ° C., Ac ₂ O (25.10 μl, 0.266 mmol) is added and the mixture is stirred for 10 minutes. Warmed to room temperature and stirred for 0.5 h. After stirring, saturated NaHCO ₃ solution (10.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (140.2 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 50: 1: 0.1) to give EM960 (132.0 mg, 100%) as a white powder.

EM960

HR-MS mlz: 768.4538 [M + Na] ⁺ , C ₃₈ H ₆₇ NO ₁₃ Na calcd: 768.4510 [M + Na]

Example  61

Synthesis of de (3'-N-methyl) -9-dihydro-3'-N-methanesulfonyl- pseudoerythromycin A 6.9-epoxide (EM961)

Under an N ₂ atmosphere, a solution of CH ₂ Cl ₂ (3.040 mL) of EM901 (107.0 mg, 0.152 mmol) was cooled to 0 ° C., MsCl (23.50 μl, 0.304 mmol) was added and the mixture was stirred for 0.5 h, Warm to room temperature and stir for 1.5 hours. After stirring, MsCl (47.00 μl, 0.608 mmol) was added and the mixture was stirred for 4 hours. After stirring, saturated NaHCO ₃ solution (20.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (111.1 mg). The crude product obtained was isolated by flash column chromatography fatigue purification (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 50: 1: 0.1) to give EM961 (75.80 mg, 64%) as a white powder.

EM961

HR-MS m / z: 804.4183 [M + Na] ⁺ , C ₃₇ H ₆₇ NO ₁₄ SNa calcd: 804.4180 [M + Na]

Example  62

Synthesis of de (3'-N-methyl) -9-dihydro-3'-N-n-pentyl- pseudoerythromycin A 6,9-epoxide (EM962)

Under N ₂ atmosphere, EM901 (131.5 mg, 0.189 mmol) in a 1,2-dichloroethane solution (3.780 mL) was cooled to 0 ° C., n-valeraldehyde (41.10 μl, 0.387 mmol), AcOH (32.50 μl, 0.567) mmol) and NaBH (OAc) ₃ (120.2 mg, 0.567 mmol) were added and the mixture was warmed to rt and stirred for 2 h. After stirring, saturated NaHCO ₃ solution (20.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (120.5 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: NH ₄ OH aqueous solution = 50: 1: 0.1) to give EM962 (118.8 mg, 81%) as a white powder.

EM962

HR-MS m / z: 774.5383 [M + H] ⁺ , C ₄₁ H ₇₆ NO ₁₂ Calculated Value: 774.5368 [M + H]

Example  63

Synthesis of de (3'-dimethylamino) -3 '-(4 "'-N-benzyloxycarbonylpiperazinyl) -9-dihydro- pseudoerythromycin A 6,9-epoxide (EM965)

Under N ₂ atmosphere, i-Pr2NEt (537 μl, 3.08 mmol) and benzyl bis (2-bromoethyl) carbamate (760 mg, 2.08) were added to a CH ₃ CN solution (61.6 mL) of EM903 (213 mg, 0.308 mmol). mmol) was added and the mixture was stirred at 80 ° C for 12 h. After stirring, saturated Na ₂ S ₂ O ₃ solution (60.00 mL) was added and the mixture was extracted with CHCl ₃ . After washing with saturated NH ₄ Cl solution and brine, the organic layer was dried over Na ₂ SO ₄ . The residue was filtered off and the filtrate was concentrated to give crude product (250 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: 30% NH ₄ OH aqueous solution = 100: 1: 0.1) to give EM965 (169 mg, 61%) as a white powder.

IR (KBR) v cm ^-1 ; 3469, 2971, 2935, 2883, 1708, 1625, 1455, 1378, 1267, 1166, 1110, 1054, 1022

¹³ C NMR (67.5 MHz, CDCl ₃ ) δ (ppm): 177.2 (C-1), 139.1 (2C, 4 ″ ′ -N C O ₂ CH ₂ Ph, 4 ″ ′ -N CO ₂ CH ₂ Ph C − 1), 128.9 (4 "' - N CO 2 CH 2 Ph C -3,5), 128.4 (4"' - N CO 2 CH 2 Ph C -2,6), 127.1 (4 "'- N CO 2 CH ₂ Ph C -4), 104.1 (C-1 '), 97.9 (C-1 "), 83.9 (C-9), 83.2 (C-6), 82.9 (C-5), 80.5 (C-3 ), 78.1 (C-4 "), 77.3 (C-12), 75.9 (C-13), 74.8 (C-11), 72.3 (C-3"), 70.8 (C-2 '), 68.9 (C -5 '), 65.3 (2C, C-5 ", C-3'), 60.1 (4"' -N C0 ₂ C H ₂ Ph), 53.6 (2C, 3'- N ( C H ₂ CH ₂ ) ₂ NZ), 49.2 (3 " -O CH ₃ ), 46.7 (2C, C-2,3'- N (CH ₂ C H ₂ ) ₂ NZ), 41.7 (C-7), 36.6 (C-4) , 35.2 (C-2 "), 33.8 (C-10), 33.7 (C-8), 22.5 (13- C H ₂ CH ₃ ), 22.3 (6-CH ₃ ), 21.5 (3" -CH ₃ ) , 21.1 (5'-CH ₃ ), 18.0 (5 "-CH ₃ ), 17.6 (8-CH ₃ ), 16.9 (12-CH ₃ ), 16.1 (10-CH ₃ ), 14.1 (2-CH ₃ ) , 12.0 (13-CH ₂ C H ₃ ), 9.6 (4-CH ₃ )

Example  64

Synthesis of de (3'-dimethylamino) -3'-piperazinyl-9-dihydro- pseudoerythromycin A 6,9-epoxide (EM966)

Under N ₂ atmosphere, Pd (OH) ₂ (24.2 mg) and EtOH (2.70 mL) were added to EM965 (122 mg, 0.137 mmol) and the mixture was stirred for 4 h at room temperature under H ₂ atmosphere. After stirring, the mixture was concentrated to give crude product (150 mg). The obtained crude product was separated and purified by flash column chromatography (CHCl ₃ : MeOH: 30% NH ₄ OH aqueous solution = 100: 1: 0.1-50: 1: 0.1) to em966 (54.2 mg, 52%) as a white powder. Produced.

IR (KBR) v cm ^-1 ; 3451, 2973, 2935, 2884, 2786, 1706, 1631, 1457, 1382, 1270, 1166, 1078, 1018

¹³ C NMR (67.5 MHz, CDCl ₃ ) δ (ppm): 177.3 (C-1), 103.3 (C-1 ′), 98.0 (C-1 ″), 83.9 (C-9), 83.2 (C-6 ), 82.6 (C-5), 80.4 (C-3), 78.1 (C-4 "), 77.2 (C-12), 75.9 (C-13), 74.8 (C-11), 72.4 (C-3 "), 68.6 (2C, C-2 ', C-5'), 65.4 (2C, C-5", C-3 '), 52.1 (2C, 3'- N ( C H ₂ CH ₂ ) ₂ NH ), 49.1 (3 "- O CH 3), 46.6 (C-2), 41.8 (C-7), 40.6 (2C, 3'-N (CH 2 C H 2) 2 NH), 36.4 (C-4 ), 35.2 (C-2 "), 33.7 (C-10, C-8), 33.5 (C-4 '), 22.5 (13- C H ₂ CH ₃ ), 22.1 (6-CH ₃ ), 21.5 ( 3 "-CH ₃ ), 20.8 (5'-CH ₃ ), 18.1 (5" -CH ₃ ), 17.6 (8-CH ₃ ), 17.0 (12-CH ₃ ), 16.0 (10-CH ₃ ), 13.9 (2-CH ₃ ), 12.0 (13-CH ₂ C H ₃ ), 10.2 (4-CH ₃ )

Experimental Example  One

As an index of anti-inflammatory action of the compounds of the present invention, the differentiation-inducing activity of THP-1 cells was measured. The measurement was performed as shown below.

THP-1 cells (ATCC No. TIB-202) were adjusted to 2 × 10 ⁵ cells / ml concentration in medium (RPMI 1640), to which PMA was added to a final concentration of 1-2 μM and the mixture was added to a 96 well plate ( 100 μl was dispensed into each well of the well plate). A solution containing the test substance (100 μl) was added to each well by adjusting the concentration to the medium. The plate was shaken gently to stir the mixture and incubated 72-96 h under 37 ° C., 5% CO ₂ conditions. After washing each well with PBS, a medium containing SF (Nacalai Tesque), a viable cell measurement reagent, was added at 100 μl / well and the mixture was added at 37 ° C. under 5% CO _2. Incubated for 5 hours. Absorbance was measured with a plate reader.

Table 6 shows the THP-1 differentiation-inducing activity measured above. In the table, the activity value is the lowest concentration required for the test compound to exhibit 50% activity against the activity of erythromycin A 100 μM in this experiment.

Table 6

THP-1 Differentiation-Inducing Activity: The lowest concentration required for each compound to exhibit 50% activity against the activity of erythromycin A 100 μM.

Experimental Example  2

As an indicator of the therapeutic effect of the compounds of the present invention on ulcerative colitis and Crohn's disease, rats were investigated for action on trinitrobenzene sulfonate (hereinafter designated TNBS) -induced colitis.

Using 8 week-old male SD rats anesthetized with pentobarbital, fasting for at least 24 hours and watering for at least 5 hours were then injected with rectal TNBS solution of the animals. After injection, a silicone stopper was inserted into the anus and treatment was performed for 3.5-4 hours to prepare a colitis model. Two days after TNBS administration, fecal occult blood score (fecal occult blood sliede 5 shionogi II, manufactured by Shionogi & Co. Ltd.), body weight and weight changes, eating conditions, and anus Model animals were selected based on observation scores and bleeding. Test drugs were orally administered to model animals twice daily for 6 days. On the day after the last drug administration, the colon (approximately 15 cm from the anus) is removed after decapitation and exsanguination, and the degree of damage is determined by Wallace et al. (Wallace, JL et al, Inhibition of leukotriene synthesis markedly accelerates healing in A rat model of inflammatory bowel disease.Gastroenterology 96, 2936 (1989)) was used to score and assess efficacy.

The results are shown in Table 7. It has been found that the compounds of the present invention have the effect of ameliorating TNBS-induced ulcers in the colon.

Table 7

Experimental Example  3

The antimicrobial activity of the compounds of the present invention and erythromycin were measured according to the antimicrobial susceptibility measurement method of the National Council of Clinical Trials (NCCLS). The results are shown in Table 8. The minimum inhibitory concentration (MIC) values (μg / ml) for the bacteria of each compound are shown in the table. It was found that the compounds of the present invention do not have the antimicrobial activity possessed by erythromycin.

Table 8

Formulation example

The pharmaceutical compositions of the present invention may be prepared using additives for methods and formulations that are conventionally used in the art. Although typical combination examples of the pharmaceutical formulation of the present invention are shown below, the pharmaceutical composition of the present invention is not limited thereto.

(1) tablet

In one tablet, 1-500 mg of each example compound

As additives, sodium citrate, cornstarch, povidone, sodium carmellose, cellulose acetate phthalate, propylene glycol, macrogol, sorbitan fatty acid esters and castor oil are contained.

(2) ointment

10 mg (titer) of each example compound in 1 g

As additives, light liquid paraffin and white petrolatum are contained.

(3) injections

Injectable distilled water (10 ml) was added to each example compound (500 mg, titer) to give a 5% solution, diluted with glucose injection solution, saline solution (injection), etc. infusion solution).

The present invention can provide a novel dihydroshudoerythromycin derivative having excellent anti-inflammatory action and stable.

While several embodiments of the invention have been described in detail, those skilled in the art can make modifications and changes to the specific embodiments without substantially departing from the teachings and advantages of the invention. The spirit and scope of the invention as set forth in the appended claims encompasses such modifications and variations.

The present invention is based on Japanese Patent Application No. 2005-301070, the contents of which are hereby incorporated by reference in their entirety.

Claims (48)

A compound represented by the following general formula [I], or a pharmacologically acceptable salt thereof:

{Wherein Me is a methyl group, R ₁ and R ₂ are the same or different and each is a hydrogen atom, an alkyl group, an acyl group, a sulfonyl group, a substituted or unsubstituted aryl-substituted alkyl group, an aryl-substituted alkyloxycarbonyl group, an alkenyl group or an alkynyl group, or R ₁ and R the _two are combined, adjacent to form a substituted or unsubstituted alicyclic heterocyclic group together with the nitrogen atom, R ₃ is a hydrogen atom, a substituted or unsubstituted acyl group or an aryl-substituted alkyloxycarbonyl group, A is a hydrogen atom, B is a hydroxyl group or a group represented by the following formula [II]

(Wherein Me is a methyl group and R ₄ is a hydrogen atom or an acyl group), or A and B in combination represent = O, R is a group represented by the following general formula [III]

(Wherein Me is a methyl group, R ₅ and R ₆ are the same or different and each represents a hydrogen atom or an acyl group, or R ₅ and R ₆ in combination represent a carbonyl group or a substituted or unsubstituted alkylene group), Or a substituent represented by [IV]

(Wherein Me is a methyl group, D is O or N-OH, or D is a hydrogen atom and a hydroxyl group (-H, -OH)), or a substituent represented by the following formula [V]:

(Wherein Me is a methyl group)}. The compound according to claim 1, or a pharmacologically acceptable salt thereof, wherein R is a group represented by the following formula [III]:

(Wherein Me is a methyl group, R ₅ and R ₆ are the same or different and each represents a hydrogen atom or an acyl group, or R ₅ and R ₆ in combination represent a carbonyl group or a substituted or unsubstituted alkylene group). The compound according to claim 1, or a pharmacologically acceptable salt thereof, wherein A and B in combination represent = O. 3. A compound according to claim 2, or a pharmacologically acceptable salt thereof, wherein A and B in combination represent = O. The compound according to claim 1, or a pharmacologically acceptable salt thereof, wherein A is a hydrogen atom and B is a hydroxyl group. The compound according to claim 2, or a pharmacologically acceptable salt thereof, wherein A is a hydrogen atom and B is a hydroxyl group. The compound according to claim 1, or a pharmacologically acceptable salt thereof, wherein A is a hydrogen atom and B is a group represented by the following formula [II]:

(Wherein Me is a methyl group and R ₄ is a hydrogen atom or an acyl group). 3. A compound according to claim 2, or a pharmacologically acceptable salt thereof, wherein A is a hydrogen atom and B is a group represented by the following formula [II]:

(Wherein Me is a methyl group and R ₄ is a hydrogen atom or an acyl group). 8. A compound according to claim 7, or a pharmacologically acceptable salt thereof, wherein R ₄ is a hydrogen atom. The compound according to claim 8, or a pharmacologically acceptable salt thereof, wherein R ₄ is a hydrogen atom. The compound according to any one of claims 1 to 10, wherein R ₁ and R ₂ are the same or different and each is a hydrogen atom, an alkyl group, a substituted or unsubstituted benzyl group or benzyloxycarbonyl group, or a combination of R ₁ and R ₂ To form a substituted or unsubstituted alicyclic heterocyclic group with an adjacent nitrogen atom, or a pharmacologically acceptable salt thereof. The compound according to claim 11, or a pharmacologically acceptable salt thereof, wherein R ₁ and R ₂ are the same or different and each is a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms, or a halogen-substituted benzyl group. The substituted or unsubstituted alicyclic heterocyclic group formed by combining R ₁ and R ₂ together with an adjacent nitrogen atom is a substituted or unsubstituted morpholine ring, piperidine ring, piperazine ring or pipe. A compound that is a rolidine ring, or a pharmacologically acceptable salt thereof. The compound according to any one of claims 1 to 10, wherein R ₃ is a hydrogen atom, an acetyl group, a substituted or unsubstituted benzoyl group, or a benzyloxycarbonyl group, or a pharmacologically acceptable salt thereof. The compound according to claim 11, or a pharmacologically acceptable salt thereof, wherein R ₃ is a hydrogen atom, an acetyl group, a substituted or unsubstituted benzoyl group, or a benzyloxycarbonyl group. The compound according to claim 12, or a pharmacologically acceptable salt thereof, wherein R ₃ is a hydrogen atom, an acetyl group, a substituted or unsubstituted benzoyl group, or a benzyloxycarbonyl group. The compound according to claim 13, or a pharmacologically acceptable salt thereof, wherein R ₃ is a hydrogen atom, an acetyl group, a substituted or unsubstituted benzoyl group, or a benzyloxycarbonyl group. The compound according to claim 14, or a pharmacologically acceptable salt thereof, wherein R ₃ is a hydrogen atom, a substituted or unsubstituted acetyl group, or a benzoyl group. The compound according to claim 15, or a pharmacologically acceptable salt thereof, wherein R ₃ is a hydrogen atom, a substituted or unsubstituted acetyl group, or a benzoyl group. The compound according to claim 16, or a pharmacologically acceptable salt thereof, wherein R ₃ is a hydrogen atom, a substituted or unsubstituted acetyl group, or a benzoyl group. The compound according to claim 17, or a pharmacologically acceptable salt thereof, wherein R ₃ is a hydrogen atom, a substituted or unsubstituted acetyl group, or a benzoyl group. The following compounds, or pharmacologically acceptable salts thereof: (1) 9-dihydro-pseudoerythromycin A 6,9-epoxide (2) de (3'-N-methyl) -9-dihydro- pseudoerythromycin A 6,9-epoxide (3) de (3'-N-methyl) -3'-N-benzyl-9-dihydro- pseudoerythromycin A 6,9-epoxide (4) bis-de (3'-N-methyl) -9-dihydro- pseudoerythromycin A 6,9-epoxide (5) Bis-de (3'-N-methyl) -bis- (3'-N-benzyl) -9-dihydro- pseudoerythromycin A 6,9-epoxide (6) de (3'-N-methyl) -3'-N- (p-chlorobenzyl) -9-dihydro- pseudoerythromycin A 6,9-epoxide (7) de [12- (1-hydroxypropyl)]-9-dihydro-12-oxo- pseudoerythromycin A 6,9-epoxide (8) de [12- (1-hydroxypropyl)]-9-dihydro-12-hydroxyoxime- pseudoerythromycin A 6,9-epoxide (9) de [12- (1-hydroxypropyl)]-9-dihydro- pseudoerythromycin A 6,9-epoxide (10) 12,13-epoxy-9-dihydro-pseudoerythromycin A 6,9-epoxide (11) de (3-O-cladinosyl) -9-dihydro- pseudoerythromycin A 6,9-epoxide (12) 4 ", 13-O-diacetyl-9-dihydro- pseudoerythromycin A 6,9-epoxide (13) 2'-0-acetyl-9-dihydro-pseudoerythromycin A 6,9-epoxide (14) de (3'-dimethylamino) -3'-morpholino-9-dihydro-pseudoerythromycin A 6,9-epoxide (15) 2'-O-acetyl-de (3-O-cladinosyl) -9-dihydro-3-keto- pseudoerythromycin A 6,9-epoxide 12,13-carbonate (16) de (3-O-cladinosyl) -9-dihydro-3-keto- pseudoerythromycin A 6,9-epoxide 12,13-carbonate (17) de (3'-N-methyl) -3'-N- (p-chlorobenzyl) -de (3-O-cladinosyl) -9-dihydro-pseudoerythromycin A 6,9-epoxy De (18) 2'-O-acetyl-de (3-O-cladinosyl) -9-dihydro-3-keto-de (3'-dimethylamino) -3'-morpholino- pseudoerythromycin A 6,9-epoxide 12,13-carbonate (19) de (3-O-cladinosyl) -9-dihydro-3-keto-de (3'-dimethylamino) -3'-morpholino-pseudoerythromycin A 6,9-epoxide 12 , 13-carbonate (20) de (3'-N-methyl) -2'-O-3'-N-bis (benzyloxycarbonyl) -de (3-O-cladinosyl) -9-dihydro- pseudoerythromycin A 6,9-epoxide 12,13-carbonate (21) de (3'-N-methyl) -3'-N- (p-chlorobenzyl) -de (3-O-cladinosyl) -9-dihydro-3-keto- pseudoerythromycin A 6 , 9-epoxide 12,13-carbonate (22) de (3-O-cladinosyl) -9-dihydro-de (3'-dimethylamino) -3'-morpholino- pseudoerythromycin A 6,9-epoxide 12,13-carr Bonate (23) de (3'-N-methyl) -3'-N- (p-chlorobenzyl) -de (3-O-cladinosyl) -9-dihydro-3-keto- pseudoerythromycin A 6 , 9-epoxide 12,13-isopropylidene acetal or (24) de (3'-N-methyl) -3'-N- (p-chlorobenzyl) -de (3-O-cladinosyl) -9-dihydro-3-keto- pseudoerythromycin A 6 , 9-epoxide. The following compounds, or pharmacologically acceptable salts thereof: (1) 9-dihydro-pseudoerythromycin A 6,9-epoxide (2) de (3'-N-methyl) -3'-N- (p-chlorobenzyl) -9-dihydro- pseudoerythromycin A 6,9-epoxide (3) de (3'-dimethylamino) -3'-morpholino-9-dihydro-pseudoerythromycin A 6,9-epoxide or (4) de (3'-N-methyl) -3'-N- (p-chlorobenzyl) -de (3-O-cladinosyl) -9-dihydro-3-keto- pseudoerythromycin A 6 , 9-epoxide 12,13-carbonate. A pharmaceutical composition for use in the prophylaxis or treatment of an inflammatory disease comprising as an active ingredient the compound of any one of claims 1 to 10 or a pharmacologically acceptable salt thereof. A pharmaceutical composition for use in the prophylaxis or treatment of an inflammatory disease comprising the compound of claim 11 or a pharmacologically acceptable salt thereof as an active ingredient. A pharmaceutical composition for use in the prophylaxis or treatment of inflammatory diseases comprising the compound of claim 14 or a pharmacologically acceptable salt thereof as an active ingredient. A pharmaceutical composition for use in the prophylaxis or treatment of an inflammatory disease comprising the compound of claim 15 or a pharmacologically acceptable salt thereof as an active ingredient. A pharmaceutical composition for use in the prophylaxis or treatment of an inflammatory disease comprising the compound of claim 22 or 23 or a pharmacologically acceptable salt thereof as an active ingredient. The pharmaceutical composition of claim 24, wherein the inflammatory disease is inflammatory bowel disease. The pharmaceutical composition of claim 25, wherein the inflammatory disease is inflammatory bowel disease. The pharmaceutical composition according to claim 26, wherein the inflammatory disease is inflammatory bowel disease. The pharmaceutical composition of claim 27, wherein the inflammatory disease is inflammatory bowel disease. The pharmaceutical composition of claim 28, wherein the inflammatory disease is inflammatory bowel disease. Use of a compound of any one of claims 1 to 10 or a pharmacologically acceptable salt thereof for the preparation of a pharmaceutical preparation for the prophylaxis or treatment of an inflammatory disease. A method of using the compound of claim 11 or a pharmacologically acceptable salt thereof for the preparation of a pharmaceutical preparation for the prophylaxis or treatment of an inflammatory disease. A method of using the compound of claim 14 or a pharmacologically acceptable salt thereof for the preparation of a pharmaceutical preparation for the prophylaxis or treatment of an inflammatory disease. A method of using the compound of claim 15 or a pharmacologically acceptable salt thereof for the preparation of a pharmaceutical preparation for the prophylaxis or treatment of an inflammatory disease. A method of using the compound of claim 22 or 23 or a pharmacologically acceptable salt thereof for the preparation of a pharmaceutical preparation for the prophylaxis or treatment of an inflammatory disease. 35. The method of claim 34, wherein the inflammatory disease is inflammatory bowel disease. 36. The method of claim 35, wherein the inflammatory disease is inflammatory bowel disease. 37. The method of claim 36, wherein the inflammatory disease is inflammatory bowel disease. 38. The method of claim 37, wherein the inflammatory disease is inflammatory bowel disease. The method of claim 38, wherein the inflammatory disease is inflammatory bowel disease. An agent for the prophylaxis or treatment of an inflammatory disease, and the agent can be used for the prophylaxis or treatment of an inflammatory disease, comprising as an active ingredient the compound of any one of claims 1 to 10 or a pharmacologically acceptable salt thereof. Commercial package containing documentation that should be used. 12. An agent for the prophylaxis or treatment of an inflammatory disease, comprising as an active ingredient the compound of claim 11 or a pharmacologically acceptable salt thereof, and a written description that the agent can or should be used for the prophylaxis or treatment of an inflammatory disease. Commercial package. 15. An agent for the prophylaxis or treatment of an inflammatory disease, comprising as an active ingredient the compound of claim 14 or a pharmacologically acceptable salt thereof, and a written description that the agent can or should be used for the prophylaxis or treatment of an inflammatory disease. Commercial package. An agent for the prophylaxis or treatment of an inflammatory disease, comprising as an active ingredient the compound of claim 15 or a pharmacologically acceptable salt thereof, and a written description indicating that the agent can or should be used for the prophylaxis or treatment of an inflammatory disease. Commercial package. An agent for the prophylaxis or treatment of an inflammatory disease, comprising the compound of claim 22 or 23 or a pharmacologically acceptable salt thereof as an active ingredient, and that the agent can or should be used for the prophylaxis or treatment of an inflammatory disease. Commercial package with less documentation.